scholarly journals Interacting Models of Amyloid-β and Tau Proteins: An Approach to Identify Drug Targets in Alzheimer’s Disease

2021 ◽  
pp. 1-7
Author(s):  
Priya Khadgawat ◽  
J.M. Siddesha ◽  
Dharini Shashank ◽  
Shashanka K. Prasad
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Targets ◽  
Molecular Mechanisms ◽  
Amyloid Β ◽  
Tau Proteins ◽  
Current Review ◽  
The World ◽  
Associated Proteins ◽  
Made In

Alzheimer’s disease (AD) is the primary cause of dementia affecting millions each year across the world, though still remains incurable. This might be attributed to the lack of knowledge about the associated proteins, their cellular and molecular mechanisms, and the genesis of the disease. The discovery of drugs that earlier revolved around targeting the amyloid-β cascade has now been reformed with the upgraded knowledge of the cross-seeding ability of tau protein which opens new gateways for therapeutic targets. This article provides a comprehensive review of various direct and indirect connecting pathways between the two main proteins involved in development and progression of AD, enabling us to further expand our repertoire of information regarding the etiology of AD. The current review indicates the need for extensive research in this niche, thus considerable advances can be made in understanding AD which eventually helps to improve the current therapeutics against AD.

scholarly journals Deconstructing Alzheimer’s Disease: How to Bridge the Gap between Experimental Models and the Human Pathology?

2021 ◽  
Vol 22 (16) ◽  
pp. 8769
Author(s):  
Anaïs Vignon ◽  
Lucie Salvador-Prince ◽  
Sylvain Lehmann ◽  
Véronique Perrier ◽  
Joan Torrent
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Amyloid Β ◽  
Experimental Models ◽  
Tau Proteins ◽  
Human Pathology ◽  
Set Up

Discovered more than a century ago, Alzheimer’s disease (AD) is not only still present in our societies but has also become the most common dementia, with 50 million people worldwide affected by the disease. This number is expected to double in the next generation, and no cure is currently available to slow down or stop the disease progression. Recently, some advances were made due to the approval of the aducanumab treatment by the American Food and Drug Administration. The etiology of this human-specific disease remains poorly understood, and the mechanisms of its development have not been completely clarified. Several hypotheses concerning the molecular mechanisms of AD have been proposed, but the existing studies focus primarily on the two main markers of the disease: the amyloid β peptides, whose aggregation in the brain generates amyloid plaques, and the abnormally phosphorylated tau proteins, which are responsible for neurofibrillary tangles. These protein aggregates induce neuroinflammation and neurodegeneration, which, in turn, lead to cognitive and behavioral deficits. The challenge is, therefore, to create models that best reproduce this pathology. This review aims at gathering the different existing AD models developed in vitro, in cellulo, and in vivo. Many models have already been set up, but it is necessary to identify the most relevant ones for our investigations. The purpose of the review is to help researchers to identify the most pertinent disease models, from the most often used to the most recently generated and from simple to complex, explaining their specificities and giving concrete examples.

scholarly journals Investigating Pathogenetic Mechanisms of Alzheimer’s Disease by Systems Biology Approaches for Drug Discovery

2021 ◽  
Vol 22 (20) ◽  
pp. 11280
Author(s):  
Shan-Ju Yeh ◽  
Ming-Hsun Chung ◽  
Bor-Sen Chen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Targets ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Early Stage ◽  
Amyloid Β ◽  
Detection Scheme ◽  
Pathogenetic Mechanisms

Alzheimer’s disease (AD) is the most common cause of dementia, characterized by progressive cognitive decline and neurodegenerative disorder. Abnormal aggregations of intracellular neurofibrillary tangles (NFTs) and unusual accumulations of extracellular amyloid-β (Aβ) peptides are two important pathological features in AD brains. However, in spite of large-scale clinical studies and computational simulations, the molecular mechanisms of AD development and progression are still unclear. In this study, we divided all of the samples into two groups: early stage (Braak score I-–III) and later stage (Braak score IV–VI). By big database mining, the candidate genetic and epigenetic networks (GEN) have been constructed. In order to find out the real GENs for two stages of AD, we performed systems identification and system order detection scheme to prune false positives with the help of corresponding microarray data. Applying the principal network projection (PNP) method, core GENs were extracted from real GENs based on the projection values. By the annotation of KEGG pathway, we could obtain core pathways from core GENs and investigate pathogenetic mechanisms for the early and later stage of AD, respectively. Consequently, according to pathogenetic mechanisms, several potential biomarkers are identified as drug targets for multiple-molecule drug design in the treatment of AD.

Identifying Alzheimer’s Disease-related miRNA Based on Semi-clustering

2019 ◽  
Vol 19 (4) ◽  
pp. 216-223 ◽  
Author(s):  
Tianyi Zhao ◽  
Donghua Wang ◽  
Yang Hu ◽  
Ningyi Zhang ◽  
Tianyi Zang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Targets ◽  
Molecular Mechanisms ◽  
Feature Vector ◽  
Mirna Gene ◽  
Interaction Network ◽  
Gene Interaction ◽  
Proteinprotein Interaction ◽  
Synaptic Structures

Background: More and more scholars are trying to use it as a specific biomarker for Alzheimer’s Disease (AD) and mild cognitive impairment (MCI). Multiple studies have indicated that miRNAs are associated with poor axonal growth and loss of synaptic structures, both of which are early events in AD. The overall loss of miRNA may be associated with aging, increasing the incidence of AD, and may also be involved in the disease through some specific molecular mechanisms. Objective: Identifying Alzheimer’s disease-related miRNA can help us find new drug targets, early diagnosis. Materials and Methods: We used genes as a bridge to connect AD and miRNAs. Firstly, proteinprotein interaction network is used to find more AD-related genes by known AD-related genes. Then, each miRNA’s correlation with these genes is obtained by miRNA-gene interaction. Finally, each miRNA could get a feature vector representing its correlation with AD. Unlike other studies, we do not generate negative samples randomly with using classification method to identify AD-related miRNAs. Here we use a semi-clustering method ‘one-class SVM’. AD-related miRNAs are considered as outliers and our aim is to identify the miRNAs that are similar to known AD-related miRNAs (outliers). Results and Conclusion: We identified 257 novel AD-related miRNAs and compare our method with SVM which is applied by generating negative samples. The AUC of our method is much higher than SVM and we did case studies to prove that our results are reliable.

Immune modulations and immunotherapies for Alzheimer’s disease: a comprehensive review

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Sara Mahdiabadi ◽  
Sara Momtazmanesh ◽  
George Perry ◽  
Nima Rezaei
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Cognitive Outcomes ◽  
Tau Proteins ◽  
Causal Role ◽  
Wide Range ◽  
Inflammatory Drugs ◽  
Anti Inflammatory ◽  
Immune Related Genes

Abstract Alzheimer’s disease (AD), the most common cause of dementia, is characterized by progressive cognitive and memory impairment ensued from neuronal dysfunction and eventual death. Intraneuronal deposition of tau proteins and extracellular senile amyloid-β plaques have ruled as the supreme postulations of AD for a relatively long time, and accordingly, a wide range of therapeutics, especially immunotherapies have been implemented. However, none of them resulted in significant positive cognitive outcomes. Especially, the repetitive failure of anti-amyloid therapies proves the inefficiency of the amyloid cascade hypothesis, suggesting that it is time to reconsider this hypothesis. Thus, for the time being, the focus is being shifted to neuroinflammation as a third core pathology in AD. Neuroinflammation was previously considered a result of the two aforementioned phenomena, but new studies suggest that it might play a causal role in the pathogenesis of AD. Neuroinflammation can act as a double-edged sword in the pathogenesis of AD, and the activation of glial cells is indispensable for mediating such attenuating or detrimental effects. The association of immune-related genes polymorphisms with the clinical phenotype of AD as well as the protective effect of anti-inflammatory drugs like nonsteroidal anti-inflammatory drugs supports the possible causal role of neuroinflammation in AD. Here, we comprehensively review immune-based therapeutic approaches toward AD, including monoclonal antibodies and vaccines. We also discuss their efficacy and underlying reasons for shortcomings. Lastly, we highlight the capacity of modulating the neuroimmune interactions and targeting neuroinflammation as a promising opportunity for finding optimal treatments for AD.

scholarly journals Imaging and Molecular Mechanisms of Alzheimer’s Disease: A Review

2018 ◽  
Vol 19 (12) ◽  
pp. 3702 ◽  
Author(s):  
Grazia Femminella ◽  
Tony Thayanandan ◽  
Valeria Calsolaro ◽  
Klara Komici ◽  
Giuseppe Rengo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Multimodal Imaging ◽  
Molecular Mechanisms ◽  
Imaging Techniques ◽  
Structural Mri ◽  
Imaging Biomarkers ◽  
Significant Burden ◽  
Made In

Alzheimer’s disease is the most common form of dementia and is a significant burden for affected patients, carers, and health systems. Great advances have been made in understanding its pathophysiology, to a point that we are moving from a purely clinical diagnosis to a biological one based on the use of biomarkers. Among those, imaging biomarkers are invaluable in Alzheimer’s, as they provide an in vivo window to the pathological processes occurring in Alzheimer’s brain. While some imaging techniques are still under evaluation in the research setting, some have reached widespread clinical use. In this review, we provide an overview of the most commonly used imaging biomarkers in Alzheimer’s disease, from molecular PET imaging to structural MRI, emphasising the concept that multimodal imaging would likely prove to be the optimal tool in the future of Alzheimer’s research and clinical practice.

Neuroprotective Role of Diosgenin, A NGF Stimulator, Against Aβ (1–42) Induced Neurotoxicity in Animal Model of Alzheimer’s Disease

2021 ◽  
Author(s):  
Swati Som ◽  
Justin Antony ◽  
Palanisamy Dhanabal ◽  
Ponnusankar Sivasankaran
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Learning And Memory ◽  
Spatial Learning ◽  
Molecular Mechanisms ◽  
Protective Action ◽  
Amyloid Β ◽  
Spatial Learning And Memory ◽  
Avoidance Task ◽  
Model Of Alzheimer’S Disease

Abstract Diosgenin is a neurosteroid derived from the plants and has been previously reported for its numerous health beneficial properties, such as anti-arrhythmic, hypolipidemic, and antiproliferative effects. Although several studies conducted earlier suggested cognition enhancement actions of diosgenin against neurodegenerative disorders, but the molecular mechanisms underlying are not clearly understood. In the present study, we investigated the neuroprotective effect of diosgenin in the wistar rats that received an intracerebroventricular injection of Amyloid-β (1–42) peptides, representing a rodent model of Alzheimer’s disease (AD). Animals were treated with 100 and 200 mg/kg/p.o of diosgenin for 28 days, followed by Amyloid-β (1–42) peptides infusion. Animals were assessed for the spatial learning and memory by using radial arm maze and passive avoidance task. Subsequently, animals were euthanized and brains were collected for biochemical estimations and histopathological studies. Our results revealed that, diosgenin administration dose dependently improved the spatial learning and memory and protected the animals from Amyloid-β (1–42) peptides induced disrupted cognitive functions. Further, biochemical analysis showed that diosgenin successfully attenuated Amyloid-β (1–42) mediated plaque load, oxidative stress, neuroinflammation and elevated acetylcholinesterase activity. In addition, histopathological evaluation also supported neuroprotective effects of diosgenin in hippocampus of rat brain when assessed using hematoxylin-eosin and Cresyl Violet staining. Thus, the aforementioned effects suggested protective action of diosgenin against Aβ (1–42) induced neuronal damage and thereby can serve as a potential therapeutic candidate for AD.

scholarly journals Molecular and Imaging Biomarkers in Alzheimer’s Disease: A Focus on Recent Insights

2020 ◽  
Vol 10 (3) ◽  
pp. 61 ◽  
Author(s):  
Chiara Villa ◽  
Marialuisa Lavitrano ◽  
Elena Salvatore ◽  
Romina Combi
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Biological Fluids ◽  
Imaging Techniques ◽  
Amyloid Β ◽  
The Elderly ◽  
Diagnostic Methods ◽  
Imaging Biomarkers ◽  
Attractive Alternative

Alzheimer’s disease (AD) is the most common neurodegenerative disease among the elderly, affecting millions of people worldwide and clinically characterized by a progressive and irreversible cognitive decline. The rapid increase in the incidence of AD highlights the need for an easy, efficient and accurate diagnosis of the disease in its initial stages in order to halt or delay the progression. The currently used diagnostic methods rely on measures of amyloid-β (Aβ), phosphorylated (p-tau) and total tau (t-tau) protein levels in the cerebrospinal fluid (CSF) aided by advanced neuroimaging techniques like positron emission tomography (PET) and magnetic resonance imaging (MRI). However, the invasiveness of these procedures and the high cost restrict their utilization. Hence, biomarkers from biological fluids obtained using non-invasive methods and novel neuroimaging approaches provide an attractive alternative for the early diagnosis of AD. Such biomarkers may also be helpful for better understanding of the molecular mechanisms underlying the disease, allowing differential diagnosis or at least prolonging the pre-symptomatic stage in patients suffering from AD. Herein, we discuss the advantages and limits of the conventional biomarkers as well as recent promising candidates from alternative body fluids and new imaging techniques.

Time for a New Strategy in the War on Alzheimer’s Disease

2019 ◽  
Vol 29 (4) ◽  
pp. 119-122
Author(s):  
Matt Kaeberlein
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Well Being ◽  
Developed Countries ◽  
Biological Aging ◽  
Root Cause ◽  
New Strategy ◽  
New Strategies ◽  
Made In

Abstract Alzheimer’s disease is a growing threat to the economic and social well-being of developed countries around the globe, but efforts to delay, prevent, or cure this disorder have yet to yield success. I believe the lack of progress largely results from approaches that ignore the most important component of Alzheimer’s disease: biological aging. Major advances have been made in understanding the molecular mechanisms that link biological aging to disease. These mechanisms have been formalized as nine hallmarks, or pillars, of aging. Here, I discuss the barriers that have impaired progress and propose specific steps that can be taken to overcome these barriers. The time has come to adopt bold new strategies that tackle biological aging as the root cause of Alzheimer’s disease.

Poor Diet, Stress, and Inactivity Converge to Form a “Perfect Storm” That Drives Alzheimer’s Disease Pathogenesis

2019 ◽  
Vol 19 (2) ◽  
pp. 60-77 ◽  
Author(s):  
Anthony G. Pacholko ◽  
Caitlin A. Wotton ◽  
Lane K. Bekar
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Environmental Factors ◽  
Late Onset ◽  
Caloric Intake ◽  
Amyloid Β ◽  
Tau Proteins ◽  
Loss Of Function ◽  
Brain Insulin Resistance ◽  
Perfect Storm

North American incidence of Alzheimer’s disease (AD) is expected to more than double over the coming generation. Although genetic factors surrounding the production and clearance of amyloid-β and phosphorylated tau proteins are known to be responsible for a subset of early-onset AD cases, they do not explain the pathogenesis of the far more prevalent sporadic late-onset variant of the disease. It is thus likely that lifestyle and environmental factors contribute to neurodegenerative processes implicated in the pathogenesis of AD. Herein, we review evidence that (1) excess sucrose consumption induces AD-associated liver pathologies and brain insulin resistance, (2) chronic stress overdrives activity of locus coeruleus neurons, leading to loss of function (a common event in neurodegeneration), (3) high-sugar diets and stress promote the loss of neuroprotective sex hormones in men and women, and (4) Western dietary trends set the stage for a lithium-deficient state. We propose that these factors may intersect as part of a “perfect storm” to contribute to the widespread prevalence of neurodegeneration and AD. In addition, we put forth the argument that exercise and supplementation with trace lithium can counteract many of the deleterious consequences associated with excessive caloric intake and perpetual stress. We conclude that lifestyle and environmental factors likely contribute to AD pathogenesis and that simple lifestyle and dietary changes can help counteract their effects.

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