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Increase of ALCAM and VCAM-1 in the plasma predicts the Alzheimers disease.

Cell adhesion molecules (CAM) are crucial in several pathological inflammation processes in Alzheimers disease (AD). However, their potential for clinical diagnostics remains unknown. The present investigation evaluated the clinical significance of ALCAM, VCAM-1, NCAM, and ICAM-1 levels in the plasma of participants with cognitive impairment (44 patients with mild cognitive impairment, 71 patients with Alzheimers dementia, and 18 patients with other dementia) and 28 controls with normal cognitive ability. We also detected plasma levels of multiple inflammatory factors (IFN-gamma, IL-18, IL-1beta, IL-13, IL-8, IL-7, CCL11, MCP-1, TSLP, IL-10, BDNF, IL-17, IL-5, TREM-1) using Multiplex liquid chip and plasma levels of Abeta1-42 and Abeta1-40 using liquid-phase flow cytometry (FCM). Our findings demonstrated a correlation of ALCAM and VCAM-1 with age, the severity of cognitive decline, and MTA, but no significant difference between groups for NCAM and ICAM-1. ALCAM and VCAM-1 both demonstrated a positive correlation with the degree of atrophy in the medial temporal lobe structure. Further analysis revealed no significant correlation in plasma between VCAM-1, ALCAM and Abeta1-40, Abeta1-42. Nevertheless, there was a significant correlation between VCAM-1, ALCAM and many inflammatory factors. Furthermore, the predictive value of ALCAM and VCAM-1 for AD was assessed using a multi-parameter regression model. ALCAM and VCAM-1 in combination with ApoE4, education, age, and MMSE could predict AD with high precision (AUC0.891 AIC146.9) without imaging diagnosis. ALCAM and VCAM-1 combination improved the predictive accuracy significantly. In a nutshell, these findings revealed ALCAM and VCAM-1 as reliable indicators of Alzheimers disease.

New prospects on cerebellar reserve Remarks on neuroprotective effects of experience in animals and humans.

The ability of the brain to change structure and function in response to experience accounts for its ability to successfully adapt to the environment in both learning processes and unique phases, such as during development and repair. On this basis, the occurrence of the brain, cognitive, and neural reserves has been advanced to explain the discrepancies between the extent of neurological damage and the severity of clinical manifestations described in patients with different life span experiences. Research on this topic highlighted the neuroprotective role of complex stimulations, allowing the brain to better cope with the damage. This framework was initially developed by observing patients with Alzheimers disease, and it has since been progressively expanded to multifarious pathological states. The cerebellum is known to be particularly responsive to experience through extensive plastic rearrangements. The neuroprotective value exerted by reserve mechanisms appears to be suitable for basic neuronal plasticity in the cerebellum. Thus, it is of primary interest to deepen our understanding of how life experiences modify individuals cerebellar morphology and functionality. The present study is aimed at analyzing the evidence provided on this topic by animal and human studies. For animals, we considered the studies in which subjects were submitted to enhanced stimulations before the damage occurred. For humans, we considered studies in which previous lifelong high-level experiences were associated with superior cerebellar abilities to cope with injury. Detailed indications of the processes underlying cerebellar reserves may be important in proposing effective interventions for patients suffering from pathologies that directly or indirectly damage cerebellar functionality.

Nicotinamide as potential biomarker for Alzheimers disease A translational study based on metabolomics.

A multimodal fusion method for Alzheimers disease based on DCT convolutional sparse representation.

The medical information contained in magnetic resonance imaging (MRI) and positron emission tomography (PET) has driven the development of intelligent diagnosis of Alzheimers disease (AD) and multimodal medical imaging. To solve the problems of severe energy loss, low contrast of fused images and spatial inconsistency in the traditional multimodal medical image fusion methods based on sparse representation. A multimodal fusion algorithm for Alzheimer s disease based on the discrete cosine transform (DCT) convolutional sparse representation is proposed. The algorithm first performs a multi-scale DCT decomposition of the source medical images and uses the sub-images of different scales as training images, respectively. Different sparse coefficients are obtained by optimally solving the sub-dictionaries at different scales using alternating directional multiplication method (ADMM). Secondly, the coefficients of high-frequency and low-frequency subimages are inverse DCTed using an improved L1 parametric rule combined with improved spatial frequency novel sum-modified SF (NMSF) to obtain the final fused images. Through extensive experimental results, we show that our proposed method has good performance in contrast enhancement, texture and contour information retention.

Alzheimers disease (AD) is the most common aged-related neurodegenerative disorder that is associated with the toxic amyloid-β (Aβ) aggregation in the brain. While the efficacies of available drugs against AD are still limited, natural products have been shown to possess neuroprotective potential for prevention and therapy of AD. This study aimed to investigate the neuroprotective effects of Whole bodies (WB) and body wall (BW) of Alzheimers disease, Neurodegenerative disorder, Traditional medicine, Experimental model systems, Molecular biology.

COVID-19 pandemic and mental healthcare Impact on health insurance with guaranteed universal access in Chile.

Universal health coverage (UHC) is a goal of the member states of the United Nations. The negative impact of the COVID-19 pandemic on mental health, inequalities in access to care, and financing gaps set a problematic scenario for universal mental health coverage. In Latin America, depression and anxiety disorders have increased by more than 30%. Chile implemented a reform for UHC in 2005 generating a mandatory guaranteed plan for health insurance (GES) that covers schizophrenia, depression, bipolar disorders, and Alzheimers disease. We assume that the pandemic increased cases of mental illness in GES of public and private insurance. This study aimed to explore the effects of the pandemic on the use of the GES mental health plan of public and private insurance. A descriptive analysis of secondary data from public and private insurance on the use and expenditure of the GES plan in mental illness between 2005 and 2020 was carried out. An aggregate analysis of the use of psychiatric consultations without a guaranteed plan and sick leave was performed. Between 2005 and 2020, 18.5% of GES cases corresponded to four mental health illnesses (1,682,021 cases). Public insurance covered 80% of cases. In the pandemic, cases of mental illness fell by 10.5% in public insurance and 28.7% in private ones, reducing spending by 33 and 6.2%, respectively. Psychiatric consultations without using the GES plan doubled in 2020 in private insurance, and medical discharges due to mental illness also increased. Leave due to mental illness increased by 20% in both types of insurance. The results suggest that the demand for mental healthcare increased during the pandemic, but public and private health insurance reduced admissions to the GES universal plan for schizophrenia, depression, and bipolar disorder. A universal guaranteed plan in an individual contribution system can have essential weaknesses for people when the principles of social security are not complied with, especially concerning the solidarity of the health insurance system.

Trends in prevalence, health disparities, and early detection of dementia A 10-year nationally representative serial cross-sectional and cohort study.

To identify trends in the prevalence of mild cognitive impairment (MCI) and dementia, and to determine risk factors associated with the early detection of dementia among U.S. middle-aged and older adults. We used 10-year nationally representative longitudinal data from the Health and Retirement Study (HRS) (2006-2016). Adults aged 55 years or older were included to examine the trend. To identify the associated factors, adults aged 55 years or older in 2006 who developed MCI or dementia in subsequent waves until the 2016 wave were included. Early and late detection of dementia were identified using the Langa-Weir classification of cognitive function. Multivariate logistic regression models were used to identify factors associated with the early detection of dementia. The sample size for the analysis of the prevalence of MCI and dementia ranged from 14,935 to 16,115 in the six survey years, and 3,729 individuals were identified to determine associated factors of the early detection of dementia. Among them, participants aged 65 years or older accounted for 77.9%, and male participants accounted for 37.2%. The 10-year prevalence of MCI and dementia was 14.5 and 6.6%, respectively. We also found decreasing prevalence trends in MCI (from 14.9 to 13.6%) and dementia (from 7.4 to 6.0%) overall in the past decade. Using logistic regression controlling for the year, non-Hispanic black (MCI OR 2.83, This study found a decreasing trend in the prevalence of MCI and dementia in the past decade and associated racialethnic and gender disparities among U.S. middle-aged and older adults. Healthcare policies and strategies may be needed to address health disparities in the prevalence and take the associated factors of the early detection of dementia into account in clinical settings.

Identification of Plasma Proteomic Biomarkers in Patients with Mild Cognitive Impairment.

Plasma proteomic profiling may provide novel biomarkers for the identification of mild cognitive impairment (MCI). The early diagnosis of MCI still remains a challenging task due to its diverse origin. Currently, molecular approaches have been used to identify MCI diversified origin as its onset is governed by a variety of molecular changes. Therefore, we aimed to find out molecular alteration in plasma using proteomics in patients with MCI for early detection of prodromal Alzheimers disease (AD). To achieve this, we performed two-dimensional (2-D) gel electrophoresis coupled with MALDI-TOFMS, which is used to analyze the differentially expressed proteins. In our study, we found three significantly altered proteins. Out of three differentially expressed proteins, one was downregulated and two were upregulated in MCI individuals as compared to control. Further, In silico analysis showed that identified proteins are involved in pathways such as complement and coagulation cascades, platelet activation and AD. STRING interaction network analysis revealed that the majority of proteins including apolipoprotein E (APO-E) have a common association with Transthyretin (TTR) and fibrinogen chain beta (FGB) protein. This suggests that APO-E, TTR and FGB are the key proteins with which other proteins interact to exert other biological functions. Conclusively, these proteins showing differential expression in the plasma might be used as a potent signature in blood for the diagnosis of MCI individuals.

Deepening the understanding of CNVs on chromosome 15q11-13 by using hiPSCs An overview.

The human α7 neuronal nicotinic acetylcholine receptor gene (CHRNA7) is widely expressed in the central and peripheral nervous systems. This receptor is implicated in both brain development and adult neurogenesis thanks to its ability to mediate acetylcholine stimulus (Ach). Copy number variations (CNVs) of CHRNA7 gene have been identified in humans and are genetically linked to cognitive impairments associated with multiple disorders, including schizophrenia, bipolar disorder, epilepsy, Alzheimers disease, and others. Currently, α7 receptor analysis has been commonly performed in animal models due to the impossibility of direct investigation of the living human brain. But the use of model systems has shown that there are very large differences between humans and mice when researchers must study the CNVs and, in particular, the CNV of chromosome 15q13.3 where the CHRNA7 gene is present. In fact, human beings present genomic alterations as well as the presence of genes of recent origin that are not present in other model systems as well as they show a very heterogeneous symptomatology that is associated with both their genetic background and the environment where they live. To date, the induced pluripotent stem cells, obtained from patients carrying CNV in CHRNA7 gene, are a good

Improving disease prevention, diagnosis, and treatment using novel bionic technologies.

Increased human life expectancy, due in part to improvements in infant and childhood survival, more active lifestyles, in combination with higher patient expectations for better health outcomes, is leading to an extensive change in the number, type and manner in which health conditions are treated. Over the next decades as the global population rapidly progresses toward a super-aging society, meeting the long-term quality of care needs is forecast to present a major healthcare challenge. The goal is to ensure longer periods of good health, a sustained sense of well-being, with extended periods of activity, social engagement, and productivity. To accomplish these goals, multifunctionalized interfaces are an indispensable component of next generation medical technologies. The development of more sophisticated materials and devices as well as an improved understanding of human disease is forecast to revolutionize the diagnosis and treatment of conditions ranging from osteoarthritis to Alzheimers disease and will impact disease prevention. This review examines emerging cutting-edge bionic materials, devices and technologies developed to advance disease prevention, and medical care and treatment in our elderly population including developments in smart bandages, cochlear implants, and the increasing role of artificial intelligence and nanorobotics in medicine.

Transcriptional signature in microglia isolated from an Alzheimers disease mouse model treated with scanning ultrasound.

Transcranial scanning ultrasound combined with intravenously injected microbubbles (SUS

Alzheimers and Parkinsons disease therapies in the clinic.

Alzheimers disease (AD) and Parkinsons disease (PD) are the most prevalent neurodegenerative diseases, affecting millions and costing billions each year in the United States alone. Despite tremendous progress in developing therapeutics that manage the symptoms of these two diseases, the scientific community has yet to develop a treatment that effectively slows down, inhibits, or cures neurodegeneration. To gain a better understanding of the current therapeutic frontier for the treatment of AD and PD, we provide a review on past and present therapeutic strategies for these two major neurodegenerative disorders in the clinical trial process. We briefly recap currently US Food and Drug Administration-approved therapies, and then explore trends in clinical trials across the variables of therapy mechanism of disease intervention, administration route, use of delivery vehicle, and outcome measures, across the clinical phases over time for Drug and Biologic therapeutics. We then present the success rate of past clinical trials and analyze the intersections in therapeutic approaches for AD and PD, revealing the shift in clinical trials away from therapies targeting neurotransmitter systems that provide symptomatic relief, and towards anti-aggregation, anti-inflammatory, anti-oxidant, and regeneration strategies that aim to inhibit the root causes of disease progression. We also highlight the evolving distribution of the types of Biologic therapies investigated, and the slowly increasing yet still severe under-utilization of delivery vehicles for AD and PD therapeutics. We then briefly discuss novel preclinical strategies for treating AD and PD. Overall, this review aims to provide a succinct overview of the clinical landscape of AD and PD therapies to better understand the fields therapeutic strategy in the past and the fields evolution in approach to the present, to better inform how to effectively treat AD and PD in the future.

Neuroprotective activity of a virus-safe nanofiltered human platelet lysate depleted of extracellular vesicles in Parkinsons disease and traumatic brain injury models.

Brain administration of human platelet lysates (HPL) is a potential emerging biotherapy of neurodegenerative and traumatic diseases of the central nervous system. HPLs being prepared from pooled platelet concentrates, thereby increasing viral risks, manufacturing processes should incorporate robust virus-reduction treatments. We evaluated a 19 ± 2-nm virus removal nanofiltration process using hydrophilic regenerated cellulose hollow fibers on the properties of a neuroprotective heat-treated HPL (HPPL). Spiking experiments demonstrated >5.30 log removal of 20-22-nm non-enveloped minute virus of mice-mock particles using an immuno-quantitative polymerase chain reaction assay. The nanofiltered HPPL (NHPPL) contained a range of neurotrophic factors like HPPL. There was >2 log removal of extracellular vesicles (EVs), associated with decreased expression of pro-thrombogenic phosphatidylserine and procoagulant activity. LC-MSMS proteomics showed that ca. 80% of HPPL proteins, including neurotrophins, cytokines, and antioxidants, were still found in NHPPL, whereas proteins associated with some infections and cancer-associated pathways, pro-coagulation and EVs, were removed. NHPPL maintained intact neuroprotective activity in Lund human mesencephalic dopaminergic neuron model of Parkinsons disease (PD), stimulated the differentiation of SH-SY5Y neuronal cells and showed preserved anti-inflammatory function upon intranasal administration in a mouse model of traumatic brain injury (TBI). Therefore, nanofiltration of HPL is feasible, lowers the viral, prothrombotic and procoagulant risks, and preserves the neuroprotective and anti-inflammatory properties in neuronal pre-clinical models of PD and TBI.

Histone deacetylase inhibitors mitigate antipsychotic risperidone-induced motor side effects in aged mice and in a mouse model of Alzheimers disease.

Antipsychotic drugs are still widely prescribed to control various severe neuropsychiatric symptoms in the elderly and dementia patients although they are off-label use in the United States. However, clinical practice shows greater side effects and lower efficacy of antipsychotics for this vulnerable population and the mechanisms surrounding this aged-related sensitivity are not well understood. Our previous studies have shown that aging-induced epigenetic alterations may be involved in the increasing severity of typical antipsychotic haloperidol induced side effects in aged mice. Still, it is unknown if similar epigenetic mechanisms extend to atypical antipsychotics, which are most often prescribed to dementia patients combined with severe neuropsychiatric symptoms. In this study, we report that atypical antipsychotic risperidone also causes increased motor side effect behaviors in aged mice and 5xFAD mice. Histone deacetylase (HDAC) inhibitor Valproic Acid and Entinostat can mitigate the risperidone induced motor side effects. We further showed besides D2R, reduced expression of 5-HT2A, one of the primary atypical antipsychotic targets in the striatum of aged mice that are also mitigated by HDAC inhibitors. Finally, we demonstrate that specific histone acetylation mark H3K27 is hypoacetylated at the

Are Alzheimers and coronary artery diseases genetically related to longevity

In the last decade researchers have attempted to investigate the shared genetic architecture of longevity and age-related diseases and assess whether the increased longevity in certain people is due to protective alleles in the risk genes for a particular condition or whether there are specific longevity genes increasing the lifespan independently of age-related conditions risk genes. The aim of this study was to investigate the shared genetic component between longevity and two age-related conditions. We performed a cross-trait meta-analysis of publicly available genome-wide data for Alzheimers disease, coronary artery disease and longevity using a subset-based approach provided by the R package ASSET. Despite the lack of strong genetic correlation between longevity and the two diseases, we identified 38 genome-wide significant lead SNPs across 22 independent genomic loci. Of them 6 were found to be potentially shared among the three traits mapping to genes including In summary, we have been able to advance in the knowledge of the genetic overlap existing among longevity and the two most common age-related disorders.

The cellular model for Alzheimers disease research PC12 cells.

Alzheimers disease (AD) is a common age-related neurodegenerative disease characterized by progressive cognitive decline and irreversible memory impairment. Currently, several studies have failed to fully elucidate ADs cellular and molecular mechanisms. For this purpose, research on related cellular models may propose potential predictive models for the drug development of AD. Therefore, many cells characterized by neuronal properties are widely used to mimic the pathological process of AD, such as PC12, SH-SY5Y, and N2a, especially the PC12 pheochromocytoma cell line. Thus, this review covers the most systematic essay that used PC12 cells to study AD. We depict the cellular source, culture condition, differentiation methods, transfection methods, drugs inducing AD, general approaches (evaluation methods and metrics), and

Cell type-specific histone acetylation profiling of Alzheimers disease subjects and integration with genetics.

We profile genome-wide histone 3 lysine 27 acetylation (H3K27ac) of 3 major brain cell types from hippocampus and dorsolateral prefrontal cortex (dlPFC) of subjects with and without Alzheimers Disease (AD). We confirm that single nucleotide polymorphisms (SNPs) associated with late onset AD (LOAD) show a strong tendency to reside in microglia-specific gene regulatory elements. Despite this significant colocalization, we find that microglia harbor more acetylation changes associated with age than with amyloid-β (Aβ) load. In contrast, we detect that an oligodendrocyte-enriched glial (OEG) population contains the majority of differentially acetylated peaks associated with Aβ load. These differential peaks reside near both early onset risk genes (

Alzheimers disease (AD) is a progressive neurodegenerative brain disorder and the most common cause of dementia in the elderly. The presence of large numbers of senile plaques, neurofibrillary tangles, and cerebral atrophy is the characteristic feature of AD. Amyloid β peptide (Aβ), derived from the amyloid precursor protein (APP), is the main component of senile plaques. AD has been extensively studied using methods involving cell lines, primary cultures of neural cells, and animal models however, discrepancies have been observed between these methods. Dissociated cultures lose the brains tissue architecture, including neural circuits, glial cells, and extracellular matrix. Experiments with animal models are lengthy and require laborious monitoring of multiple parameters. Therefore, it is necessary to combine these experimental models to understand the pathology of AD. An experimental platform amenable to continuous observation and experimental manipulation is required to analyze long-term neuronal development, plasticity, and progressive neurodegenerative diseases. In the current study, we provide a practical method to slice and cultivate rodent hippocampus to investigate the cleavage of APP and secretion of Aβ in an

Cortical hyperexcitability and plasticity in Alzheimers disease developments in understanding and management.

Transcranial magnetic stimulation (TMS) is a non-invasive neurophysiological tool that provides important insights into Alzheimers Disease (AD). A significant body of work utilizing TMS techniques has explored the pathophysiological relevance of cortical hyperexcitability and plasticity in AD and their modulation in novel therapies. This review examines the technique of TMS, the use of TMS to examine specific features of cortical excitability and the use of TMS techniques to modulate cortical function. A search was performed utilizing the PubMed database to identify key studies utilizing TMS to examine cortical hyperexcitability and plasticity in Alzheimers dementia. We then translate this understanding to the study of Alzheimers disease pathophysiology, examining the underlying neurophysiologic links contributing to these twin signatures, cortical hyperexcitability and abnormal plasticity, in the cortical dysfunction characterizing AD. Finally, we examine utilization of TMS excitability to guide targeted therapies and, through the use of repetitive TMS (rTMS), modulate cortical plasticity. The examination of cortical hyperexcitability and plasticity with TMS has potential to optimize and expand the window of therapeutic interventions in AD, though remains at relatively early stage of development.

Activity of Choline Alphoscerate on Adult-Onset Cognitive Dysfunctions A Systematic Review and Meta-Analysis.

Choline alphoscerate (alpha glyceryl phosphorylcholine, α-GPC) is a choline-containing phospholipid used as a medicine or nutraceutical to improve cognitive function impairment occurring in neurological conditions including adult-onset dementia disorders. Despite its 1985 marketing authorization, there are still discrepancies between countries regarding its approval as a prescription medicine and discussions about its effectiveness. This study aimed to evaluate the efficacy of the α-GPC compound for treating cognitive impairment in patients with adult-onset neurological disorders. Relevant studies were identified by searching PubMed, Web of Science, and Embase. Studies that evaluated the effects of α-GPC alone or in combination with other compounds on adult-onset cognitive impairment reporting cognition, function, and behavior were considered. We assessed the risk of bias of selected studies using the Cochrane risk of bias tool. A total of 1,326 studies and 300 full-text articles were screened. We included seven randomized controlled trials (RCTs) and one prospective cohort study that met our eligibility criteria. We found significant effects of α-GPC in combination with donepezil on cognition 4 RCTs, mean difference (MD)1.72, 95% confidence interval (CI) 0.20 to 3.25, functional outcomes 3 RCTs, MD0.79, 95% CI 0.34 to 1.23, and behavioral outcomes 4 RCTs MD -7.61, 95% CI -10.31 to -4.91. We also observed that patients who received α-GPC had significantly better cognition than those who received either placebo or other medications MD 3.50, 95% CI 0.36 to 6.63. α-GPC alone or in combination with donepezil improved cognition, behavior, and functional outcomes among patients with neurological conditions associated with cerebrovascular injury.

Untangling the Role of TREM2 in Conjugation with Microglia in Neuronal Dysfunction A Hypothesis on a Novel Pathway in the Pathophysiology of Alzheimers Disease.

Alzheimers disease (AD) is a complex neurodegenerative disorder involving heterogenous pathophysiological characteristics, which has become a challenge to therapeutics. The major pathophysiology of AD comprises amyloid-β (Aβ), tau, oxidative stress, and apoptosis. Recent studies indicate the significance of Triggering receptor expressed on myeloid cells 2 (TREM2) and its mutant variants in AD. TREM2 are the transmembrane receptors of microglial cells that performs a broad range of physiological cell processes. Phagocytosis of Aβ is one of the physiological roles of TREM, which plays a pivotal role in AD progression. R47H, a mutant variant of TREM2, increases the risk of AD by impairing TREM2-Aβ binding. Inconclusive evidence regarding the TREM2 signaling cascade mechanism of Aβ phagocytosis motivates the current review to propose a new hypothesis. The review systematically assesses the cross talk between TREM2 and other AD pathological domains and the influence of TREM2 on amyloid and tau seeding. Disease associated microglia (DAM), a novel state of microglia with unique transcriptional and functional signatures reported in neurodegenerative conditions, also depend on the TREM2 pathway for its differentiation. DAM is suggested to have a neuroprotective role. We hypothesize that TREM2, along with its signaling adaptors and endogenous proteins, play a key role in ameliorating Aβ clearance. We indicate that TREM2 has the potential to ameliorate the Aβ burden, though with differential clearance ability and may act as a potential therapeutic target.

Microglia-Mediated Neurovascular Unit Dysfunction in Alzheimers Disease.

The neurovascular unit (NVU) is involved in the pathological changes in Alzheimers disease (AD). The NVU is a structural and functional complex that maintains microenvironmental homeostasis and metabolic balance in the central nervous system. As one of the most important components of the NVU, microglia not only induce blood-brain barrier breakdown by promoting neuroinflammation, the infiltration of peripheral white blood cells and oxidative stress but also mediate neurovascular uncoupling by inducing mitochondrial dysfunction in neurons, abnormal contraction of cerebral vessels, and pericyte loss in AD. In addition, microglia-mediated dysfunction of cellular components in the NVU, such as astrocytes and pericytes, can destroy the integrity of the NVU and lead to NVU impairment. Therefore, we review the mechanisms of microglia-mediated NVU dysfunction in AD. Furthermore, existing therapeutic advancements aimed at restoring the function of microglia and the NVU in AD are discussed. Finally, we predict the role of pericytes in microglia-mediated NVU dysfunction in AD is the hotspot in the future.

Computational Evaluation of Azadirachta indica-Derived Bioactive Compounds as Potential Inhibitors of NLRP3 in the Treatment of Alzheimers Disease.

The development of therapeutic agents against Alzheimers disease (AD) has stalled recently. Drug candidates targeting amyloid-β (Aβ) deposition have often failed clinical trials at different stages, prompting the search for novel targets for AD therapy. The NLRP3 inflammasome is an integral part of innate immunity, contributing to neuroinflammation and AD pathophysiology. Thus, it has become a promising new target for AD therapy. The study sought to study the potential of bioactive compounds derived from Azadirachta indica to inhibit the NLRP3 protein implicated in the pathophysiology of AD. Structural bioinformatics via molecular docking and density functional theory (DFT) analysis was utilized for the identification of novel NLRP3 inhibitors from A. indica bioactive compounds. The compounds were further subjected to pharmacokinetic and drug-likeness analysis. Results obtained from the compounds were compared against that of oridonin, a known NLRP3 inhibitor. The studied compounds optimally saturated the binding site of the NLRP3 NACHT domain, forming principal interactions with the different amino acids at its binding site. The studied compounds also demonstrated better bioactivity and chemical reactivity as ascertained by DFT analysis and all the compounds except 7-desacetyl-7-benzoylazadiradione, which had two violations, conformed to Lipinskis rule of five. In silico studies show that A. indica derived compounds have better inhibitory potential against NLRP3 and better pharmacokinetic profiles when compared with the reference ligand (oridonin). These compounds are thus proposed as novel NLRP3 inhibitors for the treatment of AD. Further wetlab studies are needed to confirm the potency of the studied compounds.

Emerging Roles of Meningeal Lymphatic Vessels in Alzheimers Disease.

Meningeal lymphatic vessels (mLVs), the functional lymphatic system present in the meninges, are the key drainage route responsible for the clearance of molecules, immune cells, and cellular debris from the cerebrospinal fluid and interstitial fluid into deep cervical lymph nodes. Aging and ApoE4, the two most important risk factors for Alzheimers disease (AD), induce mLV dysfunction, decrease cerebrospinal fluid influx and outflux, and exacerbate amyloid pathology and cognitive dysfunction. Dysfunction of mLVs results in the deposition of metabolic products, accelerates neuroinflammation, and promotes the release of pro-inflammatory cytokines in the brain. Thus, mLVs represent a novel therapeutic target for treating neurodegenerative and neuroinflammatory diseases. This review aims to summarize the structure and function of mLVs and to discuss the potential effect of aging and ApoE4 on mLV dysfunction, as well as their roles in the pathogenesis of AD.

From Association to Intervention The Alzheimers Disease-Associated Processes and Targets (ADAPT) Ontology.

Many putative causes and risk factors have been associated with outcomes in Alzheimers disease (AD) but all attempts at disease-modifying treatment have failed to be clinically significant. Efforts to address this association-intervention mismatch have tended to focus on the novel design of interventions. Here, we instead deal with the notion of association in depth. We introduce the concept of disease-associated process (DAP) as a flexible concept that can unite different areas of study of AD from genetics to epidemiology to identify disease-modifying targets. We sort DAPs using three properties specificity for AD, frequency in patients, and pathogenic intensity for dementia before using a literature review to apply these properties in three ways. Firstly, we describe and visualize known DAPs. Secondly, we exemplify qualitative specificity analysis with the DAPs of tau protein pathology and autophagy to reveal their differential implication in AD. Finally, we use DAP properties to define the terms risk factor, cause, and biomarker. We show how DAPs fit into our collaborative disease ontology, the Alzheimers Disease-Associated Processes and Targets (ADAPT) ontology. We argue that our theoretical system can serve as a democratic research forum, offering a more biologically adequate view of dementia than reductionist models. The ADAPT ontology is a tool that could help to ground debates around priority setting using objective criteria for the identifying of targets in AD. Further efforts are needed to address issues of how biomedical research into AD is prioritized and funded.

The Case for a Novel Therapeutic Approach to Dementia Small Molecule Hepatocyte Growth Factor (HGFMET) Positive Modulators.

An estimated 6.5 million Americans aged 65 years or older have Alzheimers disease (AD), which will grow to 13.8 million Americans by 2060. Despite the growing burden of dementia, no fundamental change in drug development for AD has been seen in > 20 years. Currently approved drugs for AD produce only modest symptomatic improvements in cognition with small effect sizes. A growing mismatch exists between the urgent need to develop effective drugs for symptomatic AD and the largely failed search for disease modification. The failure rate of clinical trials in AD is high overall, and in particular for disease-modifying therapies. Research efforts in AD have focused predominantly on amyloid-β and tau pathologies, but limiting clinical research to these classical hallmarks of the disease does not address the most urgent patient, caregiver, or societal needs. Rather, clinical research should consider the complex pathophysiology of AD. Innovative approaches are needed that provide outside-the-box thinking, and re-imagine trial design, interventions, and outcomes as well as progress in proteomics and fluid biomarker analytics for both diagnostics and disease monitoring. A new approach offering a highly specific, yet multi-pronged intervention that exerts positive modulation on the HGFMET neurotrophic system is currently being tested in mid-to-late-stage clinical trials in mild to moderate AD. Findings from such trials may provide data to support novel approaches for development of innovative drugs for treating AD at various disease stages and may offer benefits for those already symptomatic and disease alteration in AD and other neurodegenerative diseases.

Gut-derived β-amyloid Likely a centerpiece of the gut-brain axis contributing to Alzheimers pathogenesis.

Peripheral β-amyloid (Aβ), including those contained in the gut, may contribute to the formation of Aβ plaques in the brain, and gut microbiota appears to exert an impact on Alzheimers disease (AD) via the gut-brain axis, although detailed mechanisms are not clearly defined. The current study focused on uncovering the potential interactions among gut-derived Aβ in aging, gut microbiota, and AD pathogenesis. To achieve this goal, the expression levels of Aβ and several key proteins involved in Aβ metabolism were initially assessed in mouse gut, with key results confirmed in human tissue. The results demonstrated that a high level of Aβ was detected throughout the gut in both mice and human, and gut Aβ42 increased with age in wild type and mutant amyloid precursor proteinpresenilin 1 (APPPS1) mice. Next, the gut microbiome of mice was characterized by 16S rRNA sequencing, and we found the gut microbiome altered significantly in aged APPPS1 mice and fecal microbiota transplantation (FMT) of aged APPPS1 mice increased gut BACE1 and Aβ42 levels. Intra-intestinal injection of isotope or fluorescence labeled Aβ combined with vagotomy was also performed to investigate the transmission of Aβ from gut to brain. The data showed that, in aged mice, the gut Aβ42 was transported to the brain mainly via blood rather than the vagal nerve. Furthermore, FMT of APPPS1 mice induced neuroinflammation, a phenotype that mimics early AD pathology. Taken together, this study suggests that the gut is likely a critical source of Aβ in the brain, and gut microbiota can further upregulate gut Aβ production, thereby potentially contributing to AD pathogenesis.

Cognitive effects of cilostazol in Alzheimers dementia patients with peripheral arterial occlusive disease A case-control study.

Alzheimers dementia (AD) is a slowly progressing neurodegenerative disease, characterized by beta-amyloid deposition and neurofibrillary tangles. Peripheral atherosclerosis may deteriorate these processes via endothelial cell dysfunction and microvascular impairment. Cilostazol - a phosphodiesterase 3 inhibitor - is a standard treatment for peripheral arterial occlusive disease and a potential treatment for preserving cognitive function in AD patients. We aimed to determine whether cilostazol is beneficial in AD patients with peripheral arterial occlusive disease by evaluating Cognitive Abilities Screening Instrument (CASI) domains. We conducted a retrospective case-control study of 62 AD patients in Taiwan. Thirty-one patients had peripheral arterial occlusive disease and were receiving cilostazol plus acetylcholinesterase inhibitors (AchEIs) or N-methyl d-aspartate antagonists, whereas 31 others were receiving AchEIs. Therapeutic responses were measured using neuropsychological assessments. The CASI was administered at baseline and 12 months later different domains were analyzed between the groups using univariate and multivariate analyses. Age, sex, education duration, ApoE ε4 gene status, and initial Mini-Mental State Examination scores were not different between the two groups. Except for fluency, no CASI domains showed a statistical difference between the groups. A significant difference was observed in category fluency (P 0.010). In the logistic regression analysis, after adjusting for covariate effects, category fluency still showed a significant difference between the groups (P 0.013). In AD patients with peripheral arterial occlusive disease who have received Food and Drug Administration-approved pharmacotherapy, cilostazol, as an antiplatelet, may help to preserve general cognitive function, with significant preservation in category fluency. Geriatr Gerontol Int 2023 •• ••-••.

The application of alcian blue to identify astrocyte-associated amyloid plaques by using fluorescence and confocal microscopy.

Astrocytes play an essential role in the normal functioning of the nervous system and are active contributors to the pathogenesis of neurodegenerative diseases such as Alzheimers disease (AD). Therefore, to comprehend the astrocytes and amyloid plaques relationship there is a need for imaging techniques providing simultaneous visualization of astrocytes using fluorescence and amyloid plaques revealed by transmitted light microscopy. The possibility of simultaneous detection of astrocytes by immunocytochemistry (fluorescent) and amyloid plaques by cytochemical Alcian Blue (transparent) using confocal microscopy in 8-month-old 5хFAD mice samples shown. The described method supposes performing astrocytes fluorescent labelling by GFAP or S100beta and amyloid plaques staining by Alcian Blue. Proposed approach circumvents some limitations of fluorescence microscopy, such as weak fluorescence, low contrast, fluorophore broad excitationemission profile and chemical instability. The proposed technique provides high-quality resulting images of GFAPs100beta- labelled astrocytes and Alcian Blue-stained amyloid plaques. These images are appliable for prospective qualitative and quantitative three-dimensional analysis due to the z-axis scanning. Moreover, it demonstrated the formation of stable Alcian Blue staining.

Determination of affected brain regions at various stages of Alzheimers disease.

The objective of study was to explore those brain areas that were affected at each stage during the progression of Alzheimers disease (AD). Six affected brain areas were explored at mild cognitive impairment, four at first stage and six at each of second and third stage of Alzheimers disease. The common brain regions among these stages were cuneus, precuneus, calcarine cortex, middle frontal gyrus, superior frontal gyrus, and frontal superior medial gyrus. The fMRI data at the resting state of 18 AD patients who were converted from MCI to stage 3 of Alzheimers were taken from ADNI public source database. Among these patients, there were ten males and eight females. Independent component analysis was used to explore affected brain regions and an algorithm based on deep learning convolutional neural network was proposed for binary classification among the stages of Alzheimers disease. The proposed CNN model delivered 94.6 % accuracy for separating stage 1 of Alzheimers disease from mild cognitive impairment. 96.7 % accuracy was acquired to distinguish stage 2 of Alzheimers disease from mild cognitive impairment, and stage 3 of Alzheimers disease was separated from mild cognitive impairment with an accuracy of 97.8 %.

DNA methylation of the promoter region at the CREB1 binding site is a mechanism for the epigenetic regulation of brain-specific PKMζ.

Protein kinase M zeta, PKMζ, is a brain enriched kinase with a well characterized role in Long-Term Potentiation (LTP), the activity-dependent strengthening of synapses involved in long-term memory formation. However, little is known about the molecular mechanisms that maintain the tissue specificity of this kinase. Here, we characterized the epigenetic factors, mainly DNA methylation, regulating PKMζ expression in the human brain. The PRKCZ gene has an upstream promoter regulating Protein kinase C ζ (PKCζ), and an internal promoter driving PKMζ expression. A demethylated region, including a canonical CREB binding site, situated at the internal promoter was only observed in human CNS tissues. The induction of site-specific hypermethylation of this region resulted in decreased CREB1 binding and downregulation of PKMζ expression. Noteworthy, CREB binding sites were absent in the upstream promoter of PRKCZ locus, suggesting a specific mechanism for regulating PKMζ expression. These observations were validated using a system of human neuronal differentiation from induced pluripotent stem cells (iPSCs). CREB1 binding at the internal promoter was detected only in differentiated neurons, where PKMζ is expressed. The same epigenetic mechanism in the context of CREB binding site was identified in other genes involved in neuronal differentiation and LTP. Additionally, aberrant DNA hypermethylation at the internal promoter was observed in cases of Alzheimers disease, correlating with decreased expression of PKMζ in patient brains. Altogether, we present a conserved epigenetic mechanism regulating PKMζ expression and other genes enhanced in the CNS with possible implications in neuronal differentiation and Alzheimers disease.

Blood-brain barrier penetration of non-replicating SARS-CoV-2 and S1 variants of concern induce neuroinflammation which is accentuated in a mouse model of Alzheimers disease.

COVID-19 and especially Long COVID are associated with severe CNS symptoms and may place persons at risk to develop long-term cognitive impairments. Here, we show that two non-infective models of SARS-CoV-2 can cross the blood-brain barrier (BBB) and induce neuroinflammation, a major mechanism underpinning CNS and cognitive impairments, even in the absence of productive infection. The viral models cross the BBB by the mechanism of adsorptive transcytosis with the sugar N-acetylglucosamine being key. The delta and omicron variants cross the BB B faster than the other variants of concern, with peripheral tissue uptake rates also differing for the variants. Neuroinflammation induced by icv injection of S1 protein was greatly enhanced in young and especially in aged SAMP8 mice, a model of Alzheimers disease, whereas sex and obesity had little effect.

Treadmill workout activates PPARα in the hippocampus to upregulate ADAM10, decrease plaques and improve cognitive functions in 5XFAD mouse model of Alzheimers disease.

Although liver is rich in peroxisome proliferator-activated receptor α (PPARα), recently we have described the presence of PPARα in hippocampus where it is involved in non-amyloidogenic metabolism of amyloid precursor protein (APP) via ADAM10, decreasing amyloid plaques and improving memory and learning. However, mechanisms to upregulate PPARα in vivo in the hippocampus are poorly understood. Regular exercise has multiple beneficial effects on human health and here, we describe the importance of regular mild treadmill exercise in upregulating PPARα in vivo in the hippocampus of 5XFAD mouse model of Alzheimers disease. We also demonstrate that treadmill exercise remained unable to stimulate ADAM10, reduce plaque pathology and improve cognitive functions in 5XFAD

MC-RVAE Multi-channel recurrent variational autoencoder for multimodal Alzheimers disease progression modelling.

The progression of neurodegenerative diseases, such as Alzheimers Disease, is the result of complex mechanisms interacting across multiple spatial and temporal scales. Understanding and predicting the longitudinal course of the disease requires harnessing the variability across different data modalities and time, which is extremely challenging. In this paper, we propose a model based on recurrent variational autoencoders that is able to capture cross-channel interactions between different modalities and model temporal information. These are achieved thanks to its multi-channel architecture and its shared latent variational space, parametrized with a recurrent neural network. We evaluate our model on both synthetic and real longitudinal datasets, the latter including imaging and non-imaging data, with N897 subjects. Results show that our multi-channel recurrent variational autoencoder outperforms a set of baselines (KNN, random forest, and group factor analysis) for the task of reconstructing missing modalities, reducing the mean absolute error by 5% (w.r.t. the best baseline) for both subcortical volumes and cortical thickness. Our model is robust to missing features within each modality and is able to generate realistic synthetic imaging biomarkers trajectories from cognitive scores.

Liquid-liquid phase separation of amyloid-β oligomers modulates amyloid fibrils formation.

Soluble amyloid-β oligomers (AβOs) are proposed to instigate and mediate the pathology of Alzheimers disease (AD), but the mechanisms involved are not clear. In this study, we reported that AβOs can undergo liquid-liquid phase separation (LLPS) to form liquid-like droplets in vitro. We determined that AβOs exhibited an α-helix conformation in a membrane-mimicking environment of sodium dodecyl sulfate (SDS). Importantly, SDS is capable of reconfiguring the assembly of different AβOs to induce their LLPS. Moreover, we found that droplet formation of AβOs was promoted by strong hydrated anions and weak hydrated cations, suggesting that hydrophobic interactions play a key role in mediating phase separation of AβOs. Finally, we observed that LLPS of AβOs can further promote Aβ to form amyloid fibrils, which can be modulated by (-)-epigallocatechin gallate (EGCG). Our study highlights amyloid oligomers as an important entity involved in protein liquid-to-solid phase transition and reveals the regulatory role of LLPS underlying amyloid protein aggregation, which may be relevant to the pathological process of AD.

Repurposing digoxin for geroprotection in patients with frailty and multimorbidity.

The geroscience hypothesis proposes biological hallmarks of ageing are modifiable. Increasing evidence supports targeting these hallmarks with therapeutics could prevent and ameliorate age-related conditions - collectively termed geroprotector drugs. Cellular senescence is a hallmark with considerable potential to be modified with geroprotector drugs. Senotherapeutics are drugs that target cellular senescence for therapeutic benefit. Repurposing commonly used medications with secondary geroprotector properties is a strategy of interest to promote incorporation of geroprotector drugs into clinical practice. One candidate is the cardiac glycoside digoxin. Evidence in mouse models of pulmonary fibrosis, Alzheimers disease, arthritis and atherosclerosis support digoxin as a senotherapeutic agent. Proposed senolytic mechanisms are upregulation of intrinsic apoptotic pathways and promoting intracellular acidification. Digoxin also appears to have a senomorphic mechanism - altering the T cell pool to ameliorate pro-inflammatory SASP. Despite being widely prescribed to treat atrial fibrillation and heart failure, often in multimorbid older adults, it is not known whether digoxin exerts senotherapeutic effects in humans. Further cellular and animal studies, and ultimately clinical trials with participation of pre-frail older adults, are required to identify whether digoxin has senotherapeutic effect at low dose. This paper reviews the biological mechanisms identified in preliminary cellular and animal studies that support repurposing digoxin as a geroprotector in patients with frailty and multimorbidity.

Hippocampal subfield viscoelasticity in amnestic mild cognitive impairment evaluated with MR elastography.

Hippocampal subfields (HCsf) are brain regions important for memory function that are vulnerable to decline with amnestic mild cognitive impairment (aMCI), which is often a preclinical stage of Alzheimers disease. Studies in aMCI patients often assess HCsf tissue integrity using measures of volume, which has little specificity to microstructure and pathology. We use magnetic resonance elastography (MRE) to examine the viscoelastic mechanical properties of HCsf tissue, which is related to structural integrity, and sensitively detect differences in older adults with aMCI compared to an age-matched control group. Group comparisons revealed HCsf viscoelasticity is differentially affected in aMCI, with CA1-CA2 and DG-CA3 exhibiting lower stiffness and CA1-CA2 exhibiting higher damping ratio, both indicating poorer tissue integrity in aMCI. Including HCsf stiffness in a logistic regression improves classification of aMCI beyond measures of volume alone. Additionally, lower DG-CA3 stiffness predicted aMCI status regardless of DG-CA3 volume. These findings showcase the benefit of using MRE in detecting subtle pathological tissue changes in individuals with aMCI via the HCsf particularly affected in the disease.

Novel neuroprotective pyromeconic acid derivatives with concurrent anti-Aβ deposition, anti-inflammatory, and anti-oxidation properties for treatment of Alzheimers disease.

We synthesized a series of novel pyromeconic acid-styrene hybrid compounds and measured their activities in inhibiting Aβ

Ganoapplins A and B with an unprecedented 66656-fused pentacyclic skeleton from Ganoderma inhibit Tau pathology through activating autophagy.

Ganoapplins A and B (1 and 2) with a 66656-fused pentacyclic skeleton containing an aromatic E ring, were obtained from Ganoderma applanatum. Their structures were established through extensive spectroscopic analyses, quantum chemical calculations, including calculated chemical shifts with DP4 analysis and electronic circular dichroism (ECD). A plausible biosynthetic pathway for 1 and 2 was proposed. Furthermore, their roles in activating autophagy were investigated and the cellular assays showed that 1 and 2 can inhibit tau pathology by inducing autophagy, suggesting their potential against Alzheimers disease (AD).

Nanosensors for the diagnosis and therapy of neurodegenerative disorders and inflammatory bowel disease.

One of the areas of science which has immensely advanced in the recent years is nanotechnology. This area broadly revolves around matter at scales between 1 and 100 nm, where peculiar phenomena make way for cutting-edge applications. Today, nanotechnology has a daily impact on human life with numerous and varied possible advantages. Nanosensors are one of the products of nanotechnology and any sensor that uses nanoscale phenomena qualifies to be known as a nanosensor. Nanosensors have proven very useful in a number of sectors including medical applications, food quality analysis and agricultural controlling process, etc. One of the major human healthcare applications of nanosensors is for disease diagnosis. With the aid of nanosensors, numerous neurodegenerative disorders and inflammatory diseases are commonly identified and treated of late. Alzheimers disease (AD) and inflammatory bowel disease fall under the categories of neurodegenerative illnesses and inflammatory diseases. There are more than 20 million cases of (AD) making it the most prevalent neurological condition globally and inflammatory bowel disease (IBD) refers to a variety of conditions that cause persistent inflammation of the digestive tract. Here we present a comprehensive account on the utility of nanosensors for the diagnosis and treatment of (AD) and (IBD).

Genetic control of RNA editing in neurodegenerative disease.

A-to-I RNA editing diversifies human transcriptome to confer its functional effects on the downstream genes or regulations, potentially involving in neurodegenerative pathogenesis. Its variabilities are attributed to multiple regulators, including the key factor of genetic variants. To comprehensively investigate the potentials of neurodegenerative disease-susceptibility variants from the view of A-to-I RNA editing, we analyzed matched genetic and transcriptomic data of 1596 samples across nine brain tissues and whole blood from two large consortiums, Accelerating Medicines Partnership-Alzheimers Disease and Parkinsons Progression Markers Initiative. The large-scale and genome-wide identification of 95 198 RNA editing quantitative trait loci revealed the preferred genetic effects on adjacent editing events. Furthermore, to explore the underlying mechanisms of the genetic controls of A-to-I RNA editing, several top RNA-binding proteins were pointed out, such as EIF4A3, U2AF2, NOP58, FBL, NOP56 and DHX9, since their regulations on multiple RNA-editing events were probably interfered by these genetic variants. Moreover, these variants may also contribute to the variability of other molecular phenotypes associated with RNA editing, including the functions of 3 proteins, expressions of 277 genes and splicing of 449 events. All the analyses results shown in NeuroEdQTL (httpsrelab.xidian.edu.cnNeuroEdQTL) constituted a unique resource for the understanding of neurodegenerative pathogenesis from genotypes to phenotypes related to A-to-I RNA editing.

Chemiexcitation Mammalian Photochemistry in the Dark

Light is one way to excite an electron in biology. Another is chemiexcitation, birthing a reaction product in an electronically excited state rather than exciting from the ground state. Chemiexcited molecules, as in bioluminescence, can release more energy than ATP. Excited states also allow bond rearrangements forbidden in ground states. Molecules with low-lying unoccupied orbitals, abundant in biology, are particularly susceptible. In mammals, chemiexcitation was discovered to transfer energy from excited melanin, neurotransmitters, or hormones to DNA, creating the lethal and carcinogenic cyclobutane pyrimidine dimer. That process was initiated by nitric oxide and superoxide, radicals triggered by ultraviolet light or inflammation. Several poorly understood chronic diseases share two properties inflammation generates those radicals across the tissue, and cells that die are those containing melanin or neuromelanin. Chemiexcitation may therefore be a pathogenic event in noise- and drug-induced deafness, Parkinsons disease, and Alzheimers it may prevent macular degeneration early in life but turn pathogenic later. Beneficial evolutionary selection for excitable biomolecules may thus have conferred an Achilles heel. This review of recent findings on chemiexcitation in mammalian cells also describes the underlying physics, biochemistry, and potential pathogenesis, with the goal of making this interdisciplinary phenomenon accessible to researchers within each field.

Repetitive head impacts and chronic traumatic encephalopathy are associated with TDP-43 inclusions and hippocampal sclerosis.

Hippocampal sclerosis (HS) is associated with advanced age as well as transactive response DNA-binding protein with 43 kDa (TDP-43) deposits. Both hippocampal sclerosis and TDP-43 proteinopathy have also been described in chronic traumatic encephalopathy (CTE), a neurodegenerative disease linked to exposure to repetitive head impacts (RHI). However, the prevalence of HS in CTE, the pattern of TDP-43 pathology, and associations of HS and TDP-43 with RHI are unknown. A group of participants with a history of RHI and CTE at autopsy (n 401) as well as a group with HS-aging without CTE (n 33) was examined to determine the prevalence of HS and TDP-43 inclusions in CTE and to compare the clinical and pathological features of HS and TDP-43 inclusions in CTE to HS-aging. In CTE, HS was present in 23.4%, and TDP-43 inclusions were present in 43.3% of participants. HS in CTE occurred at a relatively young age (mean 77.0 years) and was associated with a greater number of years of RHI than CTE without HS adjusting for age (p 0.029). In CTE, TDP-43 inclusions occurred frequently in the frontal cortex and occurred both with and without limbic TDP-43. Additionally, structural equation modeling demonstrated that RHI exposure years were associated with hippocampal TDP-43 inclusions (p < 0.001) through increased CTE stage (p < 0.001). Overall, RHI and the development of CTE pathology may contribute to TDP-43 deposition and hippocampal sclerosis.

Neuroprotective effect of astragalin via activating PI3KAkt-mTOR-mediated autophagy on APPPS1 mice.

As a small molecule flavonoid, astragalin (AST) has anti-inflammatory, anti-cancer, and anti-oxidation effects. However, the impact and molecular mechanism of AST in Alzheimers disease (AD) are still not clear. This study aims to investigate the neuroprotective effect and mechanism of AST on APPPS1 mice and Aβ25-35-injured HT22 cells. In this study, we found that AST ameliorated cognitive dysfunction, reduced hippocampal neuronal damage and loss, and Aβ pathology in APPPS1 mice. Subsequently, AST activated autophagy and up-regulated the levels of autophagic flux-related protein in APPPS1 mice and Aβ25-35-induced injury in HT22 cells. Interestingly, AST down-regulated the phosphorylation level of PI3KAkt-mTOR pathway-related proteins, which was reversed by autophagy inhibitors 3-Methyladenine (3-MA) or Bafilomycin A1 (Baf A1). At the same time, consistent with the impacts of Akt inhibitor MK2206 and mTOR inhibitor rapamycin, inhibited levels of autophagy in Aβ25-35-injured HT22 cells were activated by the administration of AST. Taken together, these results suggested that AST played key neuroprotective roles on AD via stimulating PI3KAkt-mTOR pathway-mediated autophagy and autophagic flux. This study revealed a new mechanism of autophagy regulation behind the neuroprotection impact of AST for AD treatment.

Physiological significance of elevated levels of lactate by exercise training in the brain and body.

For the past 200 years, lactate has been regarded as a metabolic waste end product that causes fatigue during exercise. However, lactate production is closely correlated with energy metabolism. The lactate dehydrogenase-catalyzed reaction uses protons to produce lactate, which delays ongoing metabolic acidosis. Of note, lactate production differs depending on exercise intensity and is not limited to muscles. Importantly, controlling physiological effect of lactate may be a solution to alleviating some chronic diseases. Released through exercise, lactate is an important biomarker for fat oxidation in skeletal muscles. During recovery after sustained strenuous exercise, most of the lactate accumulated during exercise is removed by direct oxidation. However, as the muscle respiration rate decreases, lactate becomes a desirable substrate for hepatic glucose synthesis. Furthermore, improvement in brain function by lactate, particularly, through the expression of vascular endothelial growth factor and brain-derived neurotrophic factor, is being increasingly studied. In addition, it is possible to improve stress-related symptoms, such as depression, by regulating the function of hippocampal mitochondria, and with an increasingly aging society, lactate is being investigated as a preventive agent for brain diseases such as Alzheimers disease. Therefore, the perception that lactate is equivalent to fatigue should no longer exist. This review focuses on the new perception of lactate and how lactate acts extensively in the skeletal muscles, heart, brain, kidney, and liver. Additionally, lactate is now used to confirm exercise performance and should be further studied to assess its impact on exercise training.

Prediction of neuropathologic lesions from clinical data.

Post-mortem analysis provides definitive diagnoses of neurodegenerative diseases however, only a few can be diagnosed during life. This study employed statistical tools and machine learning to predict 17 neuropathologic lesions from a cohort of 6518 individuals using 381 clinical features (Table S1). The multisite data allowed validation of the models robustness by splitting traintest sets by clinical sites. A similar study was performed for predicting Alzheimers disease (AD) neuropathologic change without specific comorbidities. Prediction results show high performance for certain lesions that match or exceed that of research annotation. Neurodegenerative comorbidities in addition to AD neuropathologic change resulted in compounded, but disproportionate, effects across cognitive domains as the comorbidity number increased. Certain clinical features could be strongly associated with multiple neurodegenerative diseases, others were lesion-specific, and some were divergent between lesions. Our approach could benefit clinical research, and genetic and biomarker research by enriching cohorts for desired lesions.

Robustness of CSF Aβ4240 and Aβ42P-tau181 measured using fully automated immunoassays to detect AD-related outcomes.

This study investigated the comparability of cerebrospinal fluid (CSF) cutoffs for Elecsys immunoassays for amyloid beta (Aβ)42Aβ40 or Aβ42phosphorylated tau (p-tau)181 and the effects of measurement variability when predicting Alzheimers disease (AD)-related outcomes (i.e., Aβ-positron emission tomography PET visual read and AD neuropathology). We studied 750 participants (BioFINDER study, Alzheimers Disease Neuroimaging Initiative ADNI, and University of California San Francisco UCSF). Youdens index was used to identify cutoffs and to calculate accuracy (Aβ-PET visual read as outcome). Using longitudinal variability in Aβ-negative controls, we identified a gray zone around cut-points where the risk of an inconsistent predicted outcome was >5%. For Aβ42Aβ40, cutoffs across cohorts were <0.059 (BioFINDER), <0.057 (ADNI), and <0.058 (UCSF). For Aβ42p-tau181, cutoffs were <41.90 (BioFINDER), <39.20 (ADNI), and <46.02 (UCSF). Accuracy was ≈90% for both Aβ42Aβ40 and Aβ42p-tau181 using these cutoffs. Using Aβ-PET as an outcome, 8.7% of participants fell within a gray zone interval for Aβ42Aβ40, compared to 4.5% for Aβ42p-tau181. Similar findings were observed using a measure of overall AD neuropathologic change (7.7% vs. 3.3%). In a subset with CSF and plasma Aβ4240, the number of individuals within the gray zone was ≈1.5 to 3 times greater when using plasma Aβ4240. CSF Aβ42p-tau181 was more robust to the effects of measurement variability, suggesting that it may be the preferred Elecsys-based measure in clinical practice and trials.

Unwinding the modalities of necrosome activation and necroptosis machinery in neurological diseases.

Necroptosis, a regulated form of cell death, is involved in the genesis and development of various life-threatening diseases, including cancer, neurological disorders, cardiac myopathy, and diabetes. Necroptosis initiates with the formation and activation of a necrosome complex, which consists of RIPK1, RIPK2, RIPK3, and MLKL. Emerging studies has demonstrated the regulation of the necroptosis cell death pathway through the implication of numerous post-translational modifications, namely ubiquitination, acetylation, methylation, SUMOylation, hydroxylation, and others. In addition, the negative regulation of the necroptosis pathway has been shown to interfere with brain homeostasis through the regulation of axonal degeneration, mitochondrial dynamics, lysosomal defects, and inflammatory response. Necroptosis is controlled by the activity and expression of signaling molecules, namely VEGFVEGFR, PI3KAktGSK-3β, c-Jun N-terminal kinases (JNK), ERKMAPK, and Wntβ-catenin. Herein, we briefly discussed the implication and potential of necrosome activation in the pathogenesis and progression of neurological manifestations, such as Alzheimers disease, Parkinsons disease, multiple sclerosis, traumatic brain injury, and others. Further, we present a detailed picture of natural compounds, micro-RNAs, and chemical compounds as therapeutic agents for treating neurological manifestations.

Exercise Protects Against Cognitive Injury and Inflammation in Alzheimers Disease Through Elevating miR-148a-3p.

Alzheimers disease (AD) is a chronic neurological disorder with high morbidity. Exercise is one of the effective ways to ameliorate AD. In this study, we assessed the effects of exercise on cognition and inflammation and studied the role of miR-148a-3p in AD. In 88 patients with AD, the expression of miR-148a-3p was studied using qRT-PCR. ROC curve and Pearson analysis were utilized to evaluate the roles of miR-148a-3p in AD. MWM test was conducted to investigate the effects of miR-148a-3p and exercise on cognition and memory. Moreover, inflammatory indicators were identified using an enzyme-linked immunosorbent assay. Relative luciferase levels reflected whether miR-148a-3p targeted SYNJ1. miR-148a-3p levels declined in patients with AD, indicating its potential as a biomarker. Interestingly, miR-148a-3p levels were elevated in patients with AD after exercise. MiR-148a-3p levels correlated with cognitive scores and proinflammatory levels. The cognitive situation and pro-inflammatory state were partly recovered in the mice after exercise. MiR-148a-3p silencing reversed these abovementioned tendencies. Patients with AD exhibited a low level of miR-148a-3p, which was increased after exercise. Therefore, exercise might improve the cognitive function and memory of mice with AD by upregulating miR-148a-3p.

Molecular imaging of the association between serotonin degeneration and beta-amyloid deposition in mild cognitive impairment.

Degeneration of the serotonin system has been observed in Alzheimers disease (AD) and in mild cognitive impairment (MCI). In transgenic amyloid mouse models, serotonin degeneration is detected prior to widespread cortical beta-amyloid (Aβ) deposition, also suggesting that serotonin degeneration may be observed in preclinical AD. The differences in the distribution of serotonin degeneration (reflected by the loss of the serotonin transporter, 5-HTT) relative to Aβ deposition was measured with positron emission tomography in a group of individuals with MCI and a group of healthy older adults. A multi-modal partial least squares (mmPLS) algorithm was applied to identify the spatial covariance pattern between 5-HTT availability and Aβ deposition. Forty-five individuals with MCI and 35 healthy older adults were studied, 22 and 27 of whom were included in the analyses who were amyloid positive and amyloid negative, respectively. A pattern of lower cortical, subcortical and limbic 5-HTT availability and higher cortical Aβ deposition distinguished the MCI from the healthy older control participants. Greater expression of this pattern was correlated with greater deficits in memory and executive function in the MCI group, not in the control group. A spatial covariance pattern of lower 5-HTT availability and Aβ deposition was observed to a greater extent in an MCI group relative to a control group and was associated with cognitive impairment in the MCI group. The results support the application of mmPLS to understand the neurochemical changes associated with Aβ deposition in the course of preclinical AD.

Whole blood transcript and protein abundance of the vascular endothelial growth factor family relate to cognitive performance.

The vascular endothelial growth factor (VEGF) family of genes has been implicated in the clinical development of Alzheimers Disease (AD). A previous study identified associations between gene expression of VEGF family members in the prefrontal cortex and cognitive performance and AD pathology. This study explored if those associations were also observed in the blood. Consistent with previous observations in brain tissue, higher blood gene expression of placental growth factor (PGF) was associated with a faster rate of memory decline (p0.04). Higher protein abundance of FMS-related receptor tyrosine kinase 4 (FLT4) in blood was associated with biomarker levels indicative of lower amyloid and tau pathology, opposite the direction observed in brain. Also, higher gene expression of VEGFB in blood was associated with better baseline memory (p0.008). Notably, we observed that higher gene expression of VEGFB in blood was associated with lower expression of VEGFB in the brain (r-0.19, p0.02). Together, these results suggest that the VEGFB, FLT4, and PGF alterations in the AD brain may be detectable in the blood compartment.

The Potential of NLRP3 Inflammasome as a Therapeutic Target in Neurological Diseases.

NLRP3 (NLRP3 NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome is the best-described inflammasome that plays a crucial role in the innate immune system and a wide range of diseases. The intimate association of NLRP3 with neurological disorders, including neurodegenerative diseases and strokes, further emphasizes its prominence as a clinical target for pharmacological intervention. However, after decades of exploration, the mechanism of NLRP3 activation remains indefinite. This review highlights recent advances and gaps in our insights into the regulation of NLRP3 inflammasome. Furthermore, we present several emerging pharmacological approaches of clinical translational potential targeting the NLRP3 inflammasome in neurological diseases. More importantly, despite small-molecule inhibitors of the NLRP3 inflammasome, we have focused explicitly on Chinese herbal medicine and botanical ingredients, which may be splendid therapeutics by inhibiting NLRP3 inflammasome for central nervous system disorders. We expect that we can contribute new perspectives to the treatment of neurological diseases.

The Protective Effects of Policosanol on Learning and Memory Impairments in a Male Rat Model of Alzheimers Disease.

Alzheimers disease (AD), the most common form of dementia, is characterized by a progressive decline in cognitive performance and memory formation. The present study was designed to investigate the effect of policosanol (PCO) on cognitive function, oxidative-antioxidative status, and amyloid-beta (Aβ) plaque formation in an AD rat model induced by intracerebroventricular (ICV) injection of Aβ

The inhibition of ORMDL3 prevents Alzheimers disease through ferroptosis by PERKATF4HSPA5 pathway.

Alzheimers disease (AD) is a neurodegenerative disease with high incidence and widespread attention. There is currently no clear clarification of the pathogenesis. However, ORMDL3 causes ferroptosis in AD, and the potential mechanisms remain unclear. So, this study explore the function of ORMDL3 on ferroptosis in AD and its potential regulatory mechanisms. APPswePS1dE9 mice and C57BL6 mice were induced into the mice model. The murine microglial BV-2 cells also were induced into the vitro model. In serum samples of AD mice, ORMDL3 mRNA expression levels were upregulated. The serum ORMDL3 levels expression was positively related to the ADL score or MoCA score in AD mice. The serum ORMDL3 expression level was positively related to MMSE score or Hcy levels in AD mice. The mRNA expression of ORMDL3 in the hippocampal tissue of the mice model of AD was upregulated at one, four and eight months. The protein expression of ORMDL3 was upregulated in the mice model of AD. ORMDL3 promoted Alzheimers disease, and increased oxidative response and ferroptosis in a model of AD. PERKATF4HSPA5 pathway is one important signal pathway for the effects of ORMDL3 in a model of AD. Collectively, these data suggested that RMDL3 promoted oxidative response and ferroptosis in a model of AD by the PERKATF4HSPA5 pathway, which might be a novel anticancer mechanism of ferroptosis in AD and may serve as a regulator of AD-induced ferroptosis.

Paroxysmal Slow-Wave Events Are Uncommon in Parkinsons Disease.

Parkinsons disease (PD) is currently considered to be a multisystem neurodegenerative disease that involves cognitive alterations. EEG slowing has been associated with cognitive decline in various neurological diseases, such as PD, Alzheimers disease (AD), and epilepsy, indicating cortical involvement. A novel method revealed that this EEG slowing is composed of paroxysmal slow-wave events (PSWE) in AD and epilepsy, but in PD it has not been tested yet. Therefore, this study aimed to examine the presence of PSWE in PD as a biomarker for cortical involvement. 31 PD patients, 28 healthy controls, and 18 juvenile myoclonic epilepsy (JME) patients (served as positive control), underwent four minutes of resting-state EEG. Spectral analyses were performed to identify PSWEs in nine brain regions. Mixed-model analysis was used to compare between groups and brain regions. The correlation between PSWEs and PD duration was examined using Spearmans test. No significant differences in the number of PSWEs were observed between PD patients and controls ( This study is the first to examine the temporal characteristics of EEG slowing in PD by measuring the occurrence of PSWEs. Our findings indicate that PD patients who are cognitively intact do not have electrographic manifestations of cortical involvement. However, the correlation between PSWEs and disease duration may support future studies of repeated EEG recordings along the disease course to detect early signs of cortical involvement in PD.

A Machine Learning Approach for Walking Classification in Elderly People with Gait Disorders.

Walking ability of elderly individuals, who suffer from walking difficulties, is limited, which restricts their mobility independence. The physical health and well-being of the elderly population are affected by their level of physical activity. Therefore, monitoring daily activities can help improve the quality of life. This becomes especially a huge challenge for those, who suffer from dementia and Alzheimers disease. Thus, it is of great importance for personnel in care homesrehabilitation centers to monitor their daily activities and progress. Unlike normal subjects, it is required to place the sensor on the back of this group of patients, which makes it even more challenging to detect walking from other activities. With the latest advancements in the field of health sensing and sensor technology, a huge amount of accelerometer data can be easily collected. In this study, a Machine Learning (ML) based algorithm was developed to analyze the accelerometer data collected from patients with walking difficulties, who live in one of the municipalities in Denmark. The ML algorithm is capable of accurately classifying the walking activity of these individuals with different walking abnormalities. Various statistical, temporal, and spectral features were extracted from the time series data collected using an accelerometer sensor placed on the back of the participants. The back sensor placement is desirable in patients with dementia and Alzheimers disease since they may remove visible sensors to them due to the nature of their diseases. Then, an evolutionary optimization algorithm called Particle Swarm Optimization (PSO) was used to select a subset of features to be used in the classification step. Four different ML classifiers such as k-Nearest Neighbors (kNN), Random Forest (RF), Stacking Classifier (Stack), and Extreme Gradient Boosting (XGB) were trained and compared on an accelerometry dataset consisting of 20 participants. These models were evaluated using the leave-one-group-out cross-validation (LOGO-CV) technique. The Stack model achieved the best performance with average sensitivity, positive predictive values (precision), F

Potential Anti-Cholinesterase Activity of Bioactive Compounds Extracted from

Acetylcholinesterase (AChE) inhibitors remain the primary therapeutic drug that can alleviate Alzheimers diseases (AD) symptoms. Several

Curcumin-Based Nanomedicines in the Treatment of Inflammatory and Immunomodulated Diseases An Evidence-Based Comprehensive Review.

Curcumin (CUR) is a polyphenol extracted from the rhizome of

Development and Evaluation of Solid Lipid Nanoparticles for the Clearance of Aβ in Alzheimers Disease.

Aggregation of Amyloid-β (Aβ) leads to the formation and deposition of neurofibrillary tangles and plaques which is the main pathological hallmark of Alzheimers disease (AD). The bioavailability of the drugs and their capability to cross the BBB plays a crucial role in the therapeutics of AD. The present study evaluates the Memantine Hydrochloride (MeHCl) and Tramiprosate (TMPS) loaded solid lipid nanoparticles (SLNs) for the clearance of Aβ on SHSY5Y cells in rat hippocampus. Molecular docking and in vitro Aβ fibrillation were used to ensure the binding of drugs to Aβ. The in vitro cell viability study showed that the M T SLNs showed enhanced neuroprotection against SHSY5Y cells than the pure drugs (M T PD) in presence of Aβ (80.35µM ± 0.455 µM) at a 31 molar ratio. The Box-Behnken Design (BBD) was employed to optimize the SLNs and the optimized M T SLNs were further characterized by %drug entrapment efficiency (99.24 ± 3.24 of MeHCl and 89.99 ± 0.95 of TMPS), particle size (159.9 ± 0.569 nm), PDI (0.149 ± 0.08), Zeta potential (-6.4 ± 0.948 mV), Transmission Electron Microscopy (TEM), Atomic Force Microscopy (AFM) and in vitro drug release. The TEM AFM analysis showed irregularly spherical morphology. In vitro release of SLNs was noted up to 48 h whereas the pure drugs released completely within 3 hrs. M T SLNs revealed an improved pharmacokinetic profile and a 4-fold increase in drug concentration in the brain when compared to the pure drug. Behavioral tests showed enhanced spatial memory and histological studies confirmed reduced Aβ plaques in rat hippocampus. Furthermore, the levels of Aβ decreased in AlCl

Therapeutic Potential of Natural Compounds in Neurodegenerative Diseases Insights from Clinical Trials.

Neurodegenerative diseases are caused by the gradual loss of neurons function. These neurological illnesses remain incurable, and current medicines only alleviate the symptoms. Given the social and economic burden caused by the rising frequency of neurodegenerative diseases, there is an urgent need for the development of appropriate therapeutics. Natural compounds are gaining popularity as alternatives to synthetic drugs due to their neuroprotective properties and higher biocompatibility. While natural compounds therapeutic effects for neurodegenerative disease treatment have been investigated in numerous in vitro and in vivo studies, only few have moved to clinical trials. This article provides the first systematic review of the clinical trials evaluating natural compounds safety and efficacy for the treatment of the five most prevalent neurodegenerative disorders Alzheimers disease, Parkinsons disease, multiple sclerosis, amyotrophic lateral sclerosis, and Huntingtons disease.

Indene-Derived Hydrazides Targeting Acetylcholinesterase Enzyme in Alzheimers Design, Synthesis, and Biological Evaluation.

As acetylcholinesterase (AChE) plays a crucial role in advancing Alzheimers disease (AD), its inhibition is a promising approach for treating AD. Sulindac is an NSAID of the aryl alkanoic acid class, consisting of a indene moiety, which showed neuroprotective behavior in recent studies. In this study, newer Indene analogs were synthesized and evaluated for their in vitro AChE inhibition. Additionally, compared with donepezil as the standard drug, these Indene analogs were accessed for their cell line-based toxicity study on SH-SY5Y cell line. The molecule

Docosahexaenoic Acid Ameliorates Contextual Fear Memory Deficits in the Tg2576 Alzheimers Disease Mouse Model Cellular and Molecular Correlates.

Docosahexaenoic acid (DHA), the most abundant polyunsaturated fatty acid in the brain, is essential for successful aging. In fact, epidemiological studies have demonstrated that increased intake of DHA might lower the risk for developing Alzheimers disease (AD). These observations are supported by studies in animal models showing that DHA reduces synaptic pathology and memory deficits. Different mechanisms to explain these beneficial effects have been proposed however, the molecular pathways involved are still unknown. In this study, to unravel the main underlying molecular mechanisms activated upon DHA treatment, the effect of a high dose of DHA on cognitive function and AD pathology was analyzed in aged Tg2576 mice and their wild-type littermates. Transcriptomic analysis of mice hippocampi using RNA sequencing was subsequently performed. Our results revealed that, through an amyloid-independent mechanism, DHA enhanced memory function and increased synapse formation only in the Tg2576 mice. Likewise, the IPA analysis demonstrated that essential neuronal functions related to synaptogenesis, neuritogenesis, the branching of neurites, the density of dendritic spines and the outgrowth of axons were upregulated upon-DHA treatment in Tg2576 mice. Our results suggest that memory function in APP mice is influenced by DHA intake therefore, a high dose of daily DHA should be tested as a dietary supplement for AD dementia prevention.

Physiologic Functions and Therapeutic Applications of α7 Nicotinic Acetylcholine Receptor in Brain Disorders.

Accumulating data suggest that α7 nicotinic acetylcholine receptors (α7nAChRs) are an important therapeutic target for the treatment of Alzheimers disease (AD) and schizophrenia. The homopentameric ligand-gated ion channel α7nAChR consists of five identical α7 subunits that are encoded by the

Biological Evaluation of

Alzheimers disease (AD) is a neurodegenerative disorder whose pathophysiology includes the abnormal accumulation of proteins (e.g., β-amyloid), oxidative stress, and alterations in neurotransmitter levels, mainly acetylcholine. Here we present a comparative study of the effect of extracts obtained from endemic Argentinian species of valerians, namely

Identification of a Novel Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase In Vitro and In Silico Studies.

The enhancement of cholinergic functions via acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition is considered a valuable therapeutic strategy for the treatment of Alzheimers disease. This study aimed to evaluate the in vitro effect of ZINC390718, previously filtered using computational approaches, on both cholinesterases and to characterize, using a molecular dynamics (MD) simulation, the possible binding mode of this compound inside the cholinesterase enzymes. The in vitro cytotoxicity effect was also investigated using a primary astrocyte-enriched glial cell culture. ZINC390718 presented in vitro dual inhibitory activity against AChE at a high micromolar range (IC

Identification of New

Monoamine oxidase-B (MAO-B), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) have been considered target enzymes of depression and neurodegenerative diseases, including Alzheimers disease (AD). In this study, seventeen

Exploring Mannosylpurines as Copper Chelators and Cholinesterase Inhibitors with Potential for Alzheimers Disease.

Alzheimers Disease (AD) is characterized by a progressive cholinergic neurotransmission imbalance, with a decrease of acetylcholinesterase (AChE) activity followed by a significant increase of butyrylcholinesterase (BChE) in the later AD stages. BChE activity is also crucial for the development of Aβ plaques, the main hallmarks of this pathology. Moreover, systemic copper dyshomeostasis alters neurotransmission leading to AD. In the search for structures targeting both events, a set of novel 6-benzamide purine nucleosides was synthesized, differing in glycone configuration and N

A Comparative Study of Serum Pharmacochemistry of Kai-Xin-San in Normal and AD Rats Using UPLC-LTQ-Orbitrap-MS.

Kai-Xin-San (KXS) is a classic formula for the treatment of Alzheimers disease (AD). KXS has been widely used to treat emotional diseases however, its active components remain unknown. There have been some reports about the efficacy and metabolic analysis of KXS, which are mainly based on studying normal animals. The current work first established an AD rat model by injecting D-galactose into the abdominal cavity and injecting Aβ

Characterization of Orange Peel Extract and Its Potential Protective Effect against Aluminum Chloride-Induced Alzheimers Disease.

Alzheimers disease (AD) is a devastating neurodegenerative disorder without a cure. Hence, developing an effective treatment or protective agent is crucial for public health. The present study aims to characterize orange peel extract (OPE) through in vitro and in silico studies. Furthermore, it examines the protective effect of OPE against experimentally-induced Alzheimers disease in rats. The total phenolic and flavonoid content of OPE was 255.86 ± 1.77 and 52.06 ± 1.74 (mg100 g), respectively. Gallic acid, the common polyphenol in OPE detected by HPLC was 3388.60 μg100 g. OPE antioxidant IC

Is Citicoline Effective in Preventing and Slowing Down Dementia-A Systematic Review and a Meta-Analysis.

Cognitive impairment is a staggering personal and societal burden accordingly, there is a strong interest in potential strategies for its prevention and treatment. Nutritional supplements have been extensively investigated, and citicoline seems to be a promising agent its role in clinical practice, however, has not been established. We systematically reviewed studies on the effect of citicoline on cognitive performance. We searched the PubMed and Cochrane Library databases for articles published between 2010 and 2022. Relevant information was extracted and presented following the PRISMA recommendations. Data were pooled using the inverse-variance method with random effects models. We selected seven studies including patients with mild cognitive impairment, Alzheimers disease or post-stroke dementia. All the studies showed a positive effect of citicoline on cognitive functions. Six studies could be included in the meta-analysis. Overall, citicoline improved cognitive status, with pooled standardized mean differences ranging from 0.56 (95% CI 0.37-0.75) to 1.57 (95% CI 0.77-2.37) in different sensitivity analyses. The overall quality of the studies was poor. Available data indicate that citicoline has positive effects on cognitive function. The general quality of the studies, however, is poor with significant risk of bias in favor of the intervention. Other PubMed and the Cochrane Library.

The Association of Adherence to the Mediterranean Diet with Depression in Older Adults Longitudinally Taking into Account Cognitive Status Results from the HELIAD Study.

Although research has generally shown a negative association between depression and adherence to the Mediterranean diet (MeDi), the literature related to older adults is controversial, perhaps partially due to the fact that cognitive status has not been considered. The aim of the current work was to investigate the association between MeDi and incident depression in a representative cohort of people, taking into account their cognitive status in multiple ways. The sample was drawn from the HELIAD study, a longitudinal study including a follow-up of 3 years after the baseline assessment. In total, 879 participants without depression at baseline were included (55.4% women, mean age ± Standard Deviation 73.3 ± 5.0 years). Depression was determined as a score in the Geriatric depression scale ≥6 andor antidepressant medication andor clinical diagnosis of depression. Cox proportional hazard models adjusted for age, sex and education were employed. In the basic model, adherence to the MeDi was negatively associated with depression. In the most conservative model, excluding participants with dementia and Mild Cognitive Impairment, and after controlling for the baseline Cognitive Status, each unit (range 0-55) increase in MeDi was associated with a 6.2% decrease in the risk for depression (

Development of

Radioiodinated imaging agents for Aβ amyloid plaque imaging in Alzheimers disease (AD) patients have not been actively pursued. Our previous studies employed the diaza derivatives

As aging progresses,

Drug Repurposing to Inhibit Histamine

Lower activity of the histaminergic system is associated with neurological disorders, including Alzheimers disease (AD). Thus, the enhancement of histaminergic neurotransmission by inhibition of histamine

Synthesis, DFT Studies, Molecular Docking and Biological Activity Evaluation of Thiazole-Sulfonamide Derivatives as Potent Alzheimers Inhibitors.

Alzheimers disease is a major public brain condition that has resulted in many deaths, as revealed by the World Health Organization (WHO). Conventional Alzheimers treatments such as chemotherapy, surgery, and radiotherapy are not very effective and are usually associated with several adverse effects. Therefore, it is necessary to find a new therapeutic approach that completely treats Alzheimers disease without many side effects. In this research project, we report the synthesis and biological activities of some new thiazole-bearing sulfonamide analogs (

The Association between Party Horn Use and Respiratory Function in Patients with Dementia An Experimental Study.

Informal Caregiving and Alzheimers Disease The Psychological Effect.

Latent Potential of Multifunctional Selenium Nanoparticles in Neurological Diseases and Altered Gut Microbiota.

Neurological diseases remain a major concern due to the high world mortality rate and the absence of appropriate therapies to cross the blood-brain barrier (BBB). Therefore, the major focus is on the development of such strategies that not only enhance the efficacy of drugs but also increase their permeability in the BBB. Currently, nano-scale materials seem to be an appropriate approach to treating neurological diseases based on their drug-loading capacity, reduced toxicity, targeted delivery, and enhanced therapeutic effect. Selenium (Se) is an essential micronutrient and has been of remarkable interest owing to its essential role in the physiological activity of the nervous system, i.e., signal transmission, memory, coordination, and locomotor activity. A deficiency of Se leads to various neurological diseases such as Parkinsons disease, epilepsy, and Alzheimers disease. Therefore, owing to the neuroprotective role of Se (selenium) nanoparticles (SeNPs) are of particular interest to treat neurological diseases. To date, many studies investigate the role of altered microbiota with neurological diseases thus, the current review focused not only on the recent advancement in the field of nanotechnology, considering SeNPs to cure neurological diseases, but also on investigating the potential role of SeNPs in altered microbiota.

Involvement of an Aberrant Vascular System in Neurodevelopmental, Neuropsychiatric, and Neuro-Degenerative Diseases.

The vascular system of the prenatal brain is crucial for the development of the central nervous system. Communication between vessels and neural cells is bidirectional, and dysfunctional communication can lead to neurodevelopmental diseases. In the present review, we introduce neurodevelopmental and neuropsychiatric diseases potentially caused by disturbances in the neurovascular system and discuss candidate genes responsible for neurovascular system impairments. In contrast to diseases that can manifest during the developing stage, we have also summarized the disturbances of the neurovascular system in neurodegenerative diseases including Alzheimers disease and Parkinsons disease. Furthermore, we discussed the role of abnormal vascularization and dysfunctional vessels in the development of neurovascular-related diseases.

Mediterranean Diet, Ketogenic Diet or MIND Diet for Aging Populations with Cognitive Decline A Systematic Review.

(1) Background Compelling evidence shows that dietary patterns can slow the rate of cognitive decline, suggesting diet is a promising preventive measure against dementia. (2) Objective This systematic review summarizes the evidence of three dietary patterns, the Mediterranean diet, the ketogenic diet and the MIND diet, for the prevention of cognitive decline. (3) Methods A systematic search was conducted in major electronic databases (PubMed, ScienceDirect and Web of Science) up until 31 January 2022, using the key search terms Mediterranean diet, ketogenic diet, MIND diet, dementia, cognition and aging. A statistical analysis was performed using RoB 2 and the Jadad scale to assess the risk of bias and methodological quality in randomized controlled trials. (4) Results Only RCTs were included in this study there were eleven studies (

Newly Synthesized Creatine Derivatives as Potential Neuroprotective and Antioxidant Agents on In Vitro Models of Parkinsons Disease.

Oxidative stress is one of the key factors responsible for many diseases-neurodegenerative (Parkinson and Alzheimer) diseases, diabetes, atherosclerosis, etc. Creatine, a natural amino acid derivative, is capable of exerting mild, direct antioxidant activity in cultured mammalian cells acutely injured with an array of different reactive oxygen species (ROS) generating compounds. The aim of the study was in vitro (on isolated rat brain sub-cellular fractions-synaptosomes, mitochondria and microsomes) evaluation of newly synthetized creatine derivatives for possible antioxidant and neuroprotective activity. The synaptosomes and mitochondria were obtained by multiple centrifugations with Percoll, while microsomes-only by multiple centrifugations. Varying models of oxidative stress were used to study the possible antioxidant and neuroprotective effects of the respective compounds on synaptosomes-6-hydroxydopamine on mitochondria-tert-butyl hydroperoxide and on microsomes-ironascorbate (non-enzyme-induced lipid peroxidation). Administered alone, creatine derivatives and creatine (at concentration 38 µM) revealed neurotoxic and pro-oxidant effects on isolated rat brain subcellular fractions (synaptosomes, mitochondria and microsomes). In models of 6-hydroxydopamine (on synaptosomes), tert-butyl hydroperoxide (on mitochondria) and ironascorbate (on microsomes)-induced oxidative stress, the derivatives showed neuroprotective and antioxidant effects. These effects may be due to the preservation of the reduced glutathione level, ROS scavenging and membranes stabilizers against free radicals. Thus, they play a role in the antioxidative defense system and have a promising potential as therapeutic neuroprotective agents for the treatment of neurodegenerative disorders, connected with oxidative stress, such as Parkinsons disease.

Naringin and Naringenin Polyphenols in Neurological Diseases Understandings from a Therapeutic Viewpoint.

The glycosides of two flavonoids, naringin and naringenin, are found in various citrus fruits, bergamots, tomatoes, and other fruits. These phytochemicals are associated with multiple biological functions, including neuroprotective, antioxidant, anticancer, antiviral, antibacterial, anti-inflammatory, antiadipogenic, and cardioprotective effects. The higher glutathioneoxidized glutathione ratio in 3-NP-induced rats is attributed to the ability of naringin to reduce hydroxyl radical, hydroperoxide, and nitrite. However, although progress has been made in treating these diseases, there are still global concerns about how to obtain a solution. Thus, natural compounds can provide a promising strategy for treating many neurological conditions. Possible therapeutics for neurodegenerative disorders include naringin and naringenin polyphenols. New experimental evidence shows that these polyphenols exert a wide range of pharmacological activity particular attention was paid to neurodegenerative diseases such as Alzheimers and Parkinsons diseases, as well as other neurological conditions such as anxiety, depression, schizophrenia, and chronic hyperglycemic peripheral neuropathy. Several preliminary investigations have shown promising evidence of neuroprotection. The main objective of this review was to reflect on developments in understanding the molecular mechanisms underlying the development of naringin and naringenin as potential neuroprotective medications. Furthermore, the configuration relationships between naringin and naringenin are discussed, as well as their plant sources and extraction methods.

Natural Product Co-Metabolism and the Microbiota-Gut-Brain Axis in Age-Related Diseases.

Complementary alternative medicine approaches are growing treatments of diseases to standard medicine practice. Many of these concepts are being adopted into standard practice and orthomolecular medicine. Age-related diseases, in particular neurodegenerative disorders, are particularly difficult to treat and a cure is likely a distant expectation for many of them. Shifting attention from pharmaceuticals to phytoceuticals and bugs as drugs represents a paradigm shift and novel approaches to intervention and management of age-related diseases and downstream effects of aging. Although they have their own unique pathologies, a growing body of evidence suggests Alzheimers disease (AD) and vascular dementia (VaD) share common pathology and features. Moreover, normal metabolic processes contribute to detrimental aging and age-related diseases such as AD. Recognizing the role that the cerebral and cardiovascular pathways play in AD and age-related diseases represents a common denominator in their pathobiology. Understanding how prosaic foods and medications are co-metabolized with the gut microbiota (GMB) would advance personalized medicine and represents a paradigm shift in our view of human physiology and biochemistry. Extending that advance to include a new physiology for the advanced age-related diseases would provide new treatment targets for mild cognitive impairment, dementia, and neurodegeneration and may speed up medical advancements for these particularly devastating and debilitating diseases. Here, we explore selected foods and their derivatives and suggest new dementia treatment approaches for age-related diseases that focus on reexamining the role of the GMB.

The Allosteric Antagonist of the Sigma-2 Receptors-Elayta (CT1812) as a Therapeutic Candidate for Mild to Moderate Alzheimers Disease A Scoping Systematic Review.

Nearly 35 million people worldwide live with Alzheimers disease (AD). The prevalence of the disease is expected to rise two-fold by 2050. With only symptomatic treatment options available, it is essential to understand the developments and existing evidence that aims to target brain pathology and dementia outcomes. This scoping systematic review aimed to collate existing evidence of CT1812 for use in patients with AD and summarize the methodologies of ongoing trials. Adhering to PRISMA Statement 2020 guidelines, PubMedMEDLINE, Embase, Cochrane, and ClinicalTrials.gov were systematically searched through up to 15 November 2022 by applying the following keywords CT1812, Alzheimers disease, dementia, andor sigma-2 receptor. Three completed clinical trials were included along with three ongoing records of clinical trials. The three completed trials were in Phases I and II of testing. The sample size across all three trials was 135. CT1812 reached endpoints across the trials and obtained a maximum concentration in the cerebrospinal fluid with 97-98% receptor occupancy. The findings of this systematic review must be used with caution as the results, while mostly favorable so far, must be replicated in higher-powered, placebo-controlled Phase II-III trials.

Feasibility, Acceptability, and Efficacy of Home-Based Transcranial Direct Current Stimulation on Pain in Older Adults with Alzheimers Disease and Related Dementias A Randomized Sham-Controlled Pilot Clinical Trial.

Although transcranial direct current stimulation (tDCS) is emerging as a convenient pain relief modality for several chronic pain conditions, its feasibility, acceptability, and preliminary efficacy on pain in patients with Alzheimers disease and related dementias (ADRD) have not been investigated. The purpose of this pilot study was to assess the feasibility, acceptability, and preliminary efficacy of 5, 20-min home-based tDCS sessions on chronic pain in older adults with ADRD. We randomly assigned 40 participants to active (

AmyP53 Prevents the Formation of Neurotoxic β-Amyloid Oligomers through an Unprecedent Mechanism of Interaction with Gangliosides Insights for Alzheimers Disease Therapy.

A broad range of data identify Ca

Tacrine-Based Hybrids Past, Present, and Future.

Alzheimers disease (AD) is a neurodegenerative disorder which is characterized by β-amyloid (Aβ) aggregation, τ-hyperphosphorylation, and loss of cholinergic neurons. The other important hallmarks of AD are oxidative stress, metal dyshomeostasis, inflammation, and cell cycle dysregulation. Multiple therapeutic targets may be proposed for the development of anti-AD drugs, and the one drug-multiple targets strategy is of current interest. Tacrine (THA) was the first clinically approved cholinesterase (ChE) inhibitor, which was withdrawn due to high hepatotoxicity. However, its high potency in ChE inhibition, low molecular weight, and simple structure make THA a promising scaffold for developing multi-target agents. In this review, we summarized THA-based hybrids published from 2006 to 2022, thus providing an overview of strategies that have been used in drug design and approaches that have resulted in significant cognitive improvements and reduced hepatotoxicity.

Rationale for a Multi-Factorial Approach for the Reversal of Cognitive Decline in Alzheimers Disease and MCI A Review.

Alzheimers disease (AD) is a multifactorial, progressive, neurodegenerative disease typically characterized by memory loss, personality changes, and a decline in overall cognitive function. Usually manifesting in individuals over the age of 60, this is the most prevalent type of dementia and remains the fifth leading cause of death among Americans aged 65 and older. While the development of effective treatment and prevention for AD is a major healthcare goal, unfortunately, therapeutic approaches to date have yet to find a treatment plan that produces long-term cognitive improvement. Drugs that may be able to slow down the progression rate of AD are being introduced to the market however, there has been no previous solution for preventing or reversing the disease-associated cognitive decline. Recent studies have identified several factors that contribute to the progression and severity of the disease diet, lifestyle, stress, sleep, nutrient deficiencies, mental health, socialization, and toxins. Thus, increasing evidence supports dietary and other lifestyle changes as potentially effective ways to prevent, slow, or reverse AD progression. Studies also have demonstrated that a personalized, multi-therapeutic approach is needed to improve metabolic abnormalities and AD-associated cognitive decline. These studies suggest the effects of abnormalities, such as insulin resistance, chronic inflammation, hypovitaminosis D, hormonal deficiencies, and hyperhomocysteinemia, in the AD process. Therefore a personalized, multi-therapeutic program based on an individuals genetics and biochemistry may be preferable over a single-drugmono-therapeutic approach. This article reviews these multi-therapeutic strategies that identify and attenuate all the risk factors specific to each affected individual. This article systematically reviews studies that have incorporated multiple strategies that target numerous factors simultaneously to reverse or treat cognitive decline. We included high-quality clinical trials and observational studies that focused on the cognitive effects of programs comprising lifestyle, physical, and mental activity, as well as nutritional aspects. Articles from PubMed Central, Scopus, and Google Scholar databases were collected, and abstracts were reviewed for relevance to the subject matter. Epidemiological, pathological, toxicological, genetic, and biochemical studies have all concluded that AD represents a complex network insufficiency. The research studies explored in this manuscript confirm the need for a multifactorial approach to target the various risk factors of AD. A single-drug approach may delay the progression of memory loss but, to date, has not prevented or reversed it. Diet, physical activity, sleep, stress, and environment all contribute to the progression of the disease, and, therefore, a multi-factorial optimization of network support and function offers a rational therapeutic strategy. Thus, a multi-therapeutic program that simultaneously targets multiple factors underlying the AD network may be more effective than a mono-therapeutic approach.

A Promising Strategy to Treat Neurodegenerative Diseases by SIRT3 Activation.

SIRT3, the primary mitochondrial deacetylase, regulates the functions of mitochondrial proteins including metabolic enzymes and respiratory chain components. Although SIRT3s functions in peripheral tissues are well established, the significance of its downregulation in neurodegenerative diseases is beginning to emerge. SIRT3 plays a key role in brain energy metabolism and provides substrate flexibility to neurons. It also facilitates metabolic coupling between fuel substrate-producing tissues and fuel-consuming tissues. SIRT3 mediates the health benefits of lifestyle-based modifications such as calorie restriction and exercise. SIRT3 deficiency is associated with metabolic syndrome (MetS), a precondition for diseases including obesity, diabetes, and cardiovascular disease. The pure form of Alzheimers disease (AD) is rare, and it has been reported to coexist with these diseases in aging populations. SIRT3 downregulation leads to mitochondrial dysfunction, neuroinflammation, and inflammation, potentially triggering factors of AD pathogenesis. Recent studies have also suggested that SIRT3 may act through multiple pathways to reduce plaque formation in the AD brain. In this review, we give an overview of SIRT3s roles in brain physiology and pathology and discuss several activators of SIRT3 that can be considered potential therapeutic agents for the treatment of dementia.

New Monoterpenoid Indole Alkaloids from

Eleven monoterpenoid indole alkaloids, including three new ones, tabercrassines A-C (

The Rat Brain Transcriptome From Infancy to Aging and Sporadic Alzheimers Disease-like Pathology.

It has been suggested that functional traits of the adult brain-all of which are established early in life-may affect the brains susceptibility to Alzheimers disease (AD). Results of our previous studies on senescence-accelerated OXYS rats, a model of sporadic AD, support this hypothesis. Here, to elucidate the molecular genetic nature of the aberrations revealed during brain maturation, we analyzed transcriptomes (RNA-seq data) of the prefrontal cortex (PFC) and hippocampus of OXYS rats and Wistar (control) rats in the period of brain maturation critical for OXYS rats (ages P3 and P10 P postnatal day). We found more than 1000 differentially expressed genes in both brain structures functional analysis indicated reduced efficiency of the formation of neuronal contacts, presumably explained mainly by deficits of mitochondrial functions. Next, we compared differentially expressed genes in the rat PFC and hippocampus from infancy to the progressive stage of AD-like pathology (five ages in total). Three genes (

Presenilin 1 Modulates Acetylcholinesterase Trafficking and Maturation.

In Alzheimers disease (AD), the reduction in acetylcholinesterase (AChE) enzymatic activity is not paralleled with changes in its protein levels, suggesting the presence of a considerable enzymatically inactive pool in the brain. In the present study, we validated previous findings, and, since inactive forms could result from post-translational modifications, we analyzed the glycosylation of AChE by lectin binding in brain samples from sporadic and familial AD (sAD and fAD). Most of the enzymatically active AChE was bound to lectins

Recent Advances in the Knowledge of the Mechanisms of Leptin Physiology and Actions in Neurological and Metabolic Pathologies.

Excess body weight is frequently associated with low-grade inflammation. Evidence indicates a relationship between obesity and cancer, as well as with other diseases, such as diabetes and non-alcoholic fatty liver disease, in which inflammation and the actions of various adipokines play a role in the pathological mechanisms involved in these disorders. Leptin is mainly produced by adipose tissue in proportion to fat stores, but it is also synthesized in other organs, where leptin receptors are expressed. This hormone performs numerous actions in the brain, mainly related to the control of energy homeostasis. It is also involved in neurogenesis and neuroprotection, and central leptin resistance is related to some neurological disorders, e.g., Parkinsons and Alzheimers diseases. In peripheral tissues, leptin is implicated in the regulation of metabolism, as well as of bone density and muscle mass. All these actions can be affected by changes in leptin levels and the mechanisms associated with resistance to this hormone. This review will present recent advances in the molecular mechanisms of leptin action and their underlying roles in pathological situations, which may be of interest for revealing new approaches for the treatment of diseases where the actions of this adipokine might be compromised.

Calmodulin and Amyloid Beta as Coregulators of Critical Events during the Onset and Progression of Alzheimers Disease.

Calmodulin (CaM) and a diversity of CaM-binding proteins (CaMBPs) are involved in the onset and progression of Alzheimers disease (AD). In the amyloidogenic pathway, AβPP1, BACE1 and PSEN-1 are all calcium-dependent CaMBPs as are the risk factor proteins BIN1 and TREM2. Ca

The Synergic Effect of AT(N) Profiles and Depression on the Risk of Conversion to Dementia in Patients with Mild Cognitive Impairment.

Few studies have addressed the impact of the association between Alzheimers disease (AD) biomarkers and NPSs in the conversion to dementia in patients with mild cognitive impairment (MCI), and no studies have been conducted on the interaction effect of these two risk factors. AT(N) profiles were created using AD-core biomarkers quantified in cerebrospinal fluid (CSF) (normal, brain amyloidosis, suspected non-Alzheimer pathology (SNAP) and prodromal AD). NPSs were assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q). A total of 500 individuals with MCI were followed-up yearly in a memory unit. Cox regression analysis was used to determine risk of conversion, considering additive and multiplicative interactions between AT(N) profile and NPSs on the conversion to dementia. A total of 224 participants (44.8%) converted to dementia during the 2-year follow-up study. Pathologic AT(N) groups (brain amyloidosis, prodromal AD and SNAP) and the presence of depression and apathy were associated with a higher risk of conversion to dementia. The additive combination of the AT(N) profile with depression exacerbates the risk of conversion to dementia. A synergic effect of prodromal AD profile with depressive symptoms is evidenced, identifying the most exposed individuals to conversion among MCI patients.

The Phospholipase A2 Superfamily Structure, Isozymes, Catalysis, Physiologic and Pathologic Roles.

The phospholipase A2 (PLA2) superfamily of phospholipase enzymes hydrolyzes the ester bond at the sn-2 position of the phospholipids, generating a free fatty acid and a lysophospholipid. The PLA2s are amphiphilic in nature and work only at the waterlipid interface, acting on phospholipid assemblies rather than on isolated single phospholipids. The superfamily of PLA2 comprises at least six big families of isoenzymes, based on their structure, location, substrate specificity and physiologic roles. We are reviewing the secreted PLA2 (sPLA2), cytosolic PLA2 (cPLA2), Ca

Mechanistic Insights, Treatment Paradigms, and Clinical Progress in Neurological Disorders Current and Future Prospects.

Neurodegenerative diseases (NDs) are a major cause of disability and are related to brain development. The neurological signs of brain lesions can vary from mild clinical shortfalls to more delicate and severe neurologicalbehavioral symptoms and learning disabilities, which are progressive. In this paper, we have tried to summarize a collective view of various NDs and their possible therapeutic outcomes. These diseases often occur as a consequence of the misfolding of proteins post-translation, as well as the dysfunctional trafficking of proteins. In the treatment of neurological disorders, a challenging hurdle to cross regarding drug delivery is the blood-brain barrier (BBB). The BBB plays a unique role in maintaining the homeostasis of the central nervous system (CNS) by exchanging components between the circulations and shielding the brain from neurotoxic pathogens and detrimental compounds. Here, we outline the current knowledge about BBB deterioration in the evolving brain, its origin, and therapeutic interventions. Additionally, we summarize the physiological scenarios of the BBB and its role in various cerebrovascular diseases. Overall, this information provides a detailed account of BBB functioning and the development of relevant treatments for neurological disorders. This paper will definitely help readers working in the field of neurological scientific communities.

Identification of Side Chain Oxidized Sterols as Novel Liver X Receptor Agonists with Therapeutic Potential in the Treatment of Cardiovascular and Neurodegenerative Diseases.

The nuclear receptors-liver X receptors (LXR α and β) are potential therapeutic targets in cardiovascular and neurodegenerative diseases because of their key role in the regulation of lipid homeostasis and inflammatory processes. Specific oxy(phyto)sterols differentially modulate the transcriptional activity of LXRs providing opportunities to develop compounds with improved therapeutic characteristics. We isolated oxyphytosterols from

A Genome-Wide Functional Screen Identifies Enhancer and Protective Genes for Amyloid Beta-Peptide Toxicity.

Alzheimers disease (AD) is known to be caused by amyloid β-peptide (Aβ) misfolded into β-sheets, but this knowledge has not yet led to treatments to prevent AD. To identify novel molecular players in Aβ toxicity, we carried out a genome-wide screen in

Metal Complexes as Promising Matrix Metalloproteinases Regulators.

Nowadays, cancers and dementia, such as Alzheimers disease, are the most fatal causes of death. Many studies tried to understand the pathogenesis of those diseases clearly and develop a promising way to treat the diseases. Matrix metalloproteinases (MMPs) have been reported to be involved in the pathology of cancers and AD through tumor cell movement and amyloid degradation. Therefore, control of the levels and actions of MMPs, especially MMP-2 and MMP-9, is necessary to care for andor cure cancer and AD. Various molecules have been examined for their potential application as regulators of MMPs expression and activity. Among the molecules, multiple metal complexes have shown advantages, including simple synthesis, less toxicity and specificity toward MMPs in cancer cells or in the brain. In this review, we summarize the recent studies and knowledge of metal complexes (e.g., Pt-, Ru-, Au-, Fe-, Cu-, Ni-, Zn-, and Sn-complexes) targeting MMPs and their potentials for treating andor caring the most fatal human diseases, cancers and AD.