Advances in Genetics and Epigenetic Alterations in Alzheimer’s Disease: A Notion for Therapeutic Treatment

Alzheimer’s disease (AD) is a disabling neurodegenerative disorder that leads to long-term functional and cognitive impairment and greatly reduces life expectancy. Early genetic studies focused on tracking variations in genome-wide DNA sequences discovered several polymorphisms and novel susceptibility genes associated with AD. However, despite the numerous risk factors already identified, there is still no fully satisfactory explanation for the mechanisms underlying the onset of the disease. Also, as with other complex human diseases, the causes of low heritability are unclear. Epigenetic mechanisms, in which changes in gene expression do not depend on changes in genotype, have attracted considerable attention in recent years and are key to understanding the processes that influence age-related changes and various neurological diseases. With the recent use of massive sequencing techniques, methods for studying epigenome variations in AD have also evolved tremendously, allowing the discovery of differentially expressed disease traits under different conditions and experimental settings. This is important for understanding disease development and for unlocking new potential AD therapies. In this work, we outline the genomic and epigenomic components involved in the initiation and development of AD and identify potentially effective therapeutic targets for disease control.

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Epigenetic signatures of methylated DNA cytosine in Alzheimer’s disease

Science Advances ◽

10.1126/sciadv.aaw2880 ◽

2019 ◽

Vol 5 (8) ◽

pp. eaaw2880 ◽

Cited By ~ 11

Author(s):

Irfete S. Fetahu ◽

Dingailu Ma ◽

Kimberlie Rabidou ◽

Christian Argueta ◽

Michael Smith ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Disorder ◽

Epigenetic Alterations ◽

Methylated Dna ◽

Genome Wide ◽

Hydroxymethyl Cytosine ◽

Methyl Cytosine ◽

Prognostic Implications ◽

Epigenetic Signatures

Alzheimer’s disease (AD), a progressive neurodegenerative disorder, is the most common untreatable form of dementia. Identifying molecular biomarkers that allow early detection remains a key challenge in the diagnosis, treatment, and prognostic evaluation of the disease. Here, we report a novel experimental and analytical model characterizing epigenetic alterations during AD onset and progression. We generated the first integrated base-resolution genome-wide maps of the distribution of 5-methyl-cytosine (5mC), 5-hydroxymethyl-cytosine (5hmC), and 5-formyl/carboxy-cytosine (5fC/caC) in normal and AD neurons. We identified 27 AD region–specific and 39 CpG site–specific epigenetic signatures that were independently validated across our familial and sporadic AD models, and in an independent clinical cohort. Thus, our work establishes a new model and strategy to study the epigenetic alterations underlying AD onset and progression and provides a set of highly reliable AD-specific epigenetic signatures that may have early diagnostic and prognostic implications.

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Emerging Promise of Immunotherapy for Alzheimer’s Disease: A New Hope for the Development of Alzheimer’s Vaccine

Current Topics in Medicinal Chemistry ◽

10.2174/1568026620666200422105156 ◽

2020 ◽

Vol 20 (13) ◽

pp. 1214-1234 ◽

Cited By ~ 4

Author(s):

Md. Tanvir Kabir ◽

Md. Sahab Uddin ◽

Bijo Mathew ◽

Pankoj Kumar Das ◽

Asma Perveen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Immune Response ◽

Neutralizing Antibodies ◽

Neurodegenerative Disorder ◽

Symptomatic Relief ◽

Aβ Oligomers ◽

Th2 Immune Response ◽

Age Related ◽

Anti Inflammatory

Background: Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the characteristics of this devastating disorder include the progressive and disabling deficits in the cognitive functions including reasoning, attention, judgment, comprehension, memory, and language. Objective: In this article, we have focused on the recent progress that has been achieved in the development of an effective AD vaccine. Summary: Currently, available treatment options of AD are limited to deliver short-term symptomatic relief only. A number of strategies targeting amyloid-beta (Aβ) have been developed in order to treat or prevent AD. In order to exert an effective immune response, an AD vaccine should contain adjuvants that can induce an effective anti-inflammatory T helper 2 (Th2) immune response. AD vaccines should also possess the immunogens which have the capacity to stimulate a protective immune response against various cytotoxic Aβ conformers. The induction of an effective vaccine’s immune response would necessitate the parallel delivery of immunogen to dendritic cells (DCs) and their priming to stimulate a Th2-polarized response. The aforesaid immune response is likely to mediate the generation of neutralizing antibodies against the neurotoxic Aβ oligomers (AβOs) and also anti-inflammatory cytokines, thus preventing the AD-related inflammation. Conclusion: Since there is an age-related decline in the immune functions, therefore vaccines are more likely to prevent AD instead of providing treatment. AD vaccines might be an effective and convenient approach to avoid the treatment-related huge expense.

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Inverse Correlation Between Alzheimer’s Disease and Cancer: Short Overview

Molecular Neurobiology ◽

10.1007/s12035-021-02544-1 ◽

2021 ◽

Author(s):

Agnieszka Zabłocka ◽

Wioletta Kazana ◽

Marta Sochocka ◽

Bartłomiej Stańczykiewicz ◽

Maria Janusz ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Kinase Inhibitor ◽

Fungal Infections ◽

Neurological Diseases ◽

Inverse Correlation ◽

Biological Mechanisms ◽

Age Related ◽

Common Risk Factors

AbstractThe negative association between Alzheimer’s disease (AD) and cancer suggests that susceptibility to one disease may protect against the other. When biological mechanisms of AD and cancer and relationship between them are understood, the unsolved problem of both diseases which still touches the growing human population could be overcome. Actual information about biological mechanisms and common risk factors such as chronic inflammation, age-related metabolic deregulation, and family history is presented here. Common signaling pathways, e.g., p53, Wnt, role of Pin1, and microRNA, are discussed as well. Much attention is also paid to the potential impact of chronic viral, bacterial, and fungal infections that are responsible for the inflammatory pathway in AD and also play a key role to cancer development. New data about common mechanisms in etiopathology of cancer and neurological diseases suggests new therapeutic strategies. Among them, the use of nilotinib, tyrosine kinase inhibitor, protein kinase C, and bexarotene is the most promising.

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Progressive Age-Related Impairment of the Late Long-Term Potentiation in Alzheimer's Disease Presenilin-1 Mutant Knock-in Mice

Journal of Alzheimer s Disease ◽

10.3233/jad-2010-1302 ◽

2010 ◽

Vol 19 (3) ◽

pp. 1021-1033 ◽

Cited By ~ 29

Author(s):

Alexandra Auffret ◽

Vanessa Gautheron ◽

Mark P. Mattson ◽

Jean Mariani ◽

Catherine Rovira

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Long Term Potentiation ◽

Presenilin 1 ◽

Age Related ◽

Term Potentiation

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Summary-Based Methylome-Wide Association Analyses Suggest Potential Genetically Driven Epigenetic Heterogeneity of Alzheimer’s Disease

Journal of Clinical Medicine ◽

10.3390/jcm9051489 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1489

Author(s):

Alireza Nazarian ◽

Anatoliy I. Yashin ◽

Alexander M. Kulminski

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Disorder ◽

Tissue Samples ◽

Significance Level ◽

Association Analyses ◽

Functional Studies ◽

Genome Wide ◽

Summary Data

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with no curative treatment available. Exploring the genetic and non-genetic contributors to AD pathogenesis is essential to better understand its underlying biological mechanisms, and to develop novel preventive and therapeutic strategies. We investigated potential genetically driven epigenetic heterogeneity of AD through summary data-based Mendelian randomization (SMR), which combined results from our previous genome-wide association analyses with those from two publicly available methylation quantitative trait loci studies of blood and brain tissue samples. We found that 152 probes corresponding to 113 genes were epigenetically associated with AD at a Bonferroni-adjusted significance level of 5.49E-07. Of these, 10 genes had significant probes in both brain-specific and blood-based analyses. Comparing males vs. females and hypertensive vs. non-hypertensive subjects, we found that 22 and 79 probes had group-specific associations with AD, respectively, suggesting a potential role for such epigenetic modifications in the heterogeneous nature of AD. Our analyses provided stronger evidence for possible roles of four genes (i.e., AIM2, C16orf80, DGUOK, and ST14) in AD pathogenesis as they were also transcriptionally associated with AD. The identified associations suggest a list of prioritized genes for follow-up functional studies and advance our understanding of AD pathogenesis.

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Suppression of AMD-Like Pathology by Mitochondria-Targeted Antioxidant SkQ1 Is Associated with a Decrease in the Accumulation of Amyloid β and in mTOR Activity

Antioxidants ◽

10.3390/antiox8060177 ◽

2019 ◽

Vol 8 (6) ◽

pp. 177 ◽

Cited By ~ 9

Author(s):

Natalia A. Muraleva ◽

Oyuna S. Kozhevnikova ◽

Anzhela Z. Fursova ◽

Nataliya G. Kolosova

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Β ◽

Developed Countries ◽

Term Treatment ◽

Age Related Macular Degeneration ◽

Eye Health ◽

Age Related ◽

Long Term Treatment

Age-related macular degeneration (AMD) is a major cause of irreversible visual impairment and blindness in developed countries, and the molecular pathogenesis of AMD is poorly understood. Recent studies strongly indicate that amyloid β (Aβ) accumulation —found in the brain and a defining feature of Alzheimer’s disease—also forms in the retina in both Alzheimer’s disease and AMD. The reason why highly neurotoxic proteins of consistently aggregate in the aging retina, and to what extent they contribute to AMD, remains to be fully addressed. Nonetheless, the hypothesis that Aβ is a therapeutic target in AMD is debated. Here, we showed that long-term treatment with SkQ1 (250 nmol/[kg body weight] daily from the age of 1.5 to 22 months) suppressed the development of AMD-like pathology in senescence-accelerated OXYS rats by reducing the level of Aβ and suppressing the activity of mTOR in the retina. Inhibition of mTOR signaling activity, which plays key roles in aging and age-related diseases, can be considered a new mechanism of the prophylactic effect of SkQ1. It seems probable that dietary supplementation with mitochondria-targeted antioxidant SkQ1 can be a good prevention strategy to maintain eye health and possibly a treatment of AMD.

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Relationship between Wine Consumption, Diet and Microbiome Modulation in Alzheimer’s Disease

Nutrients ◽

10.3390/nu12103082 ◽

2020 ◽

Vol 12 (10) ◽

pp. 3082

Author(s):

M. Victoria Moreno-Arribas ◽

Begoña Bartolomé ◽

José L. Peñalvo ◽

Patricia Pérez-Matute ◽

Maria José Motilva

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Gut Microbiota ◽

Neurodegenerative Disorder ◽

Current Knowledge ◽

Intestinal Microbiome ◽

Dietary Polyphenols ◽

Age Related ◽

Wine Polyphenols ◽

The Impact

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder leading to the most common form of dementia in elderly people. Modifiable dietary and lifestyle factors could either accelerate or ameliorate the aging process and the risk of developing AD and other age-related morbidities. Emerging evidence also reports a potential link between oral and gut microbiota alterations and AD. Dietary polyphenols, in particular wine polyphenols, are a major diver of oral and gut microbiota composition and function. Consequently, wine polyphenols health effects, mediated as a function of the individual’s oral and gut microbiome are considered one of the recent greatest challenges in the field of neurodegenerative diseases as a promising strategy to prevent or slow down AD progression. This review highlights current knowledge on the link of oral and intestinal microbiome and the interaction between wine polyphenols and microbiota in the context of AD. Furthermore, the extent to which mechanisms bacteria and polyphenols and its microbial metabolites exert their action on communication pathways between the brain and the microbiota, as well as the impact of the molecular mediators to these interactions on AD patients, are described.

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Repositioning of Immunomodulators: A Ray of Hope for Alzheimer’s Disease?

Frontiers in Neuroscience ◽

10.3389/fnins.2020.614643 ◽

2020 ◽

Vol 14 ◽

Author(s):

Antonio Munafò ◽

Chiara Burgaletto ◽

Giulia Di Benedetto ◽

Marco Di Mauro ◽

Rosaria Di Mauro ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Immune System ◽

Neurodegenerative Disorder ◽

Drug Repositioning ◽

Amyloid Β ◽

Deep Understanding ◽

Current Status ◽

Age Related ◽

Tnf Α

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder characterized by cognitive decline and by the presence of amyloid β plaques and neurofibrillary tangles in the brain. Despite recent advances in understanding its pathophysiological mechanisms, to date, there are no disease-modifying therapeutic options, to slow or halt the evolution of neurodegenerative processes in AD. Current pharmacological treatments only transiently mitigate the severity of symptoms, with modest or null overall improvement. Emerging evidence supports the concept that AD is affected by the impaired ability of the immune system to restrain the brain’s pathology. Deep understanding of the relationship between the nervous and the immune system may provide a novel arena to develop effective and safe drugs for AD treatment. Considering the crucial role of inflammatory/immune pathways in AD, here we discuss the current status of the immuno-oncological, immunomodulatory and anti-TNF-α drugs which are being used in preclinical studies or in ongoing clinical trials by means of the drug-repositioning approach.

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Clinical course of Alzheimer’s disease

10.1093/med/9780199569854.003.0002 ◽

2011 ◽

Author(s):

Alberto Lleo ◽

Rafael Blesa

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Daily Living ◽

Clinical Course ◽

Neurodegenerative Disorder ◽

Memory Loss ◽

Remote Memory ◽

Initial Symptom ◽

Delayed Recall ◽

Age Related

• Alzheimer’s disease is an age-related neurodegenerative disorder, with onset usually in late life, characterized by cognitive impairment, a variety of behavioural symptoms, and restrictions in the activities of daily living• The initial symptom is episodic memory loss, in particular in delayed recall of visual and/or verbal material. Immediate and remote memory is usually preserved in early stages...

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Protein Homeostasis Networks and the Use of Yeast to Guide Interventions in Alzheimer’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms21218014 ◽

2020 ◽

Vol 21 (21) ◽

pp. 8014

Author(s):

Sudip Dhakal ◽

Ian Macreadie

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Stress Responses ◽

Cell Biology ◽

Neurodegenerative Disorder ◽

The Elderly ◽

Yeast Cells ◽

Yeast Genome ◽

Protein Homeostasis ◽

Age Related

Alzheimer’s Disease (AD) is a progressive multifactorial age-related neurodegenerative disorder that causes the majority of deaths due to dementia in the elderly. Although various risk factors have been found to be associated with AD progression, the cause of the disease is still unresolved. The loss of proteostasis is one of the major causes of AD: it is evident by aggregation of misfolded proteins, lipid homeostasis disruption, accumulation of autophagic vesicles, and oxidative damage during the disease progression. Different models have been developed to study AD, one of which is a yeast model. Yeasts are simple unicellular eukaryotic cells that have provided great insights into human cell biology. Various yeast models, including unmodified and genetically modified yeasts, have been established for studying AD and have provided significant amount of information on AD pathology and potential interventions. The conservation of various human biological processes, including signal transduction, energy metabolism, protein homeostasis, stress responses, oxidative phosphorylation, vesicle trafficking, apoptosis, endocytosis, and ageing, renders yeast a fascinating, powerful model for AD. In addition, the easy manipulation of the yeast genome and availability of methods to evaluate yeast cells rapidly in high throughput technological platforms strengthen the rationale of using yeast as a model. This review focuses on the description of the proteostasis network in yeast and its comparison with the human proteostasis network. It further elaborates on the AD-associated proteostasis failure and applications of the yeast proteostasis network to understand AD pathology and its potential to guide interventions against AD.

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