scholarly journals Molecular Mechanism of Autophagy: Its Role in the Therapy of Alzheimer’s Disease

2020 ◽  
Vol 18 (8) ◽  
pp. 720-739 ◽  
Author(s):  
Yuan Zhao ◽  
Yidan Zhang ◽  
Jian Zhang ◽  
Xiangjian Zhang ◽  
Guofeng Yang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Protein Quality ◽  
Neurodegenerative Disorder ◽  
Current Knowledge ◽  
Neuritic Plaques ◽  
Progressive Dementia ◽  
Disease Modifying Therapies ◽  
Amyloid Aβ

: Alzheimer’s disease (AD) is a neurodegenerative disorder of progressive dementia that is characterized by the accumulation of beta-amyloid (Aβ)-containing neuritic plaques and intracellular Tau protein tangles. This distinctive pathology indicates that the protein quality control is compromised in AD. Autophagy functions as a “neuronal housekeeper” that eliminates aberrant protein aggregates by wrapping then into autophagosomes and delivering them to lysosomes for degradation. Several studies have suggested that autophagy deficits in autophagy participate in the accumulation and propagation of misfolded proteins (including Aβ and Tau). In this review, we summarize current knowledge of autophagy in the pathogenesis of AD, as well as some pathways targeting the restoration of autophagy. Moreover, we discuss how these aspects can contribute to the development of disease-modifying therapies in AD.

scholarly journals Alzheimer’s disease: new concepts on the role of autoimmunity and of NLRP3 inflammasome in the pathogenesis of the disease

2020 ◽  
Vol 18 ◽  
Author(s):  
Cinzia Severini ◽  
Christian Barbato ◽  
Maria Grazia Di Certo ◽  
Francesca Gabanella ◽  
Carla Petrella ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Nlrp3 Inflammasome ◽  
Neurodegenerative Disorder ◽  
Current Knowledge ◽  
Critical Factor ◽  
Innate Immune Responses ◽  
New Concepts ◽  
Amyloid Aβ

: Alzheimer’s disease (AD), recognized as the most common neurodegenerative disorder, is clinically characterized by the presence of extracellular beta amyloid (Aβ) plaques and by intracellular neurofibrillary tau tangles, accompanied by glial activation and neuroinflammation. Increasing evidence suggests that self-misfolded proteins stimulate an immune response mediated by glial cells, inducing release of inflammatory mediators and the recruitment of peripheral macrophages into the brain, which in turn aggravate AD pathology. Aim of the present review is to update the current knowledge on the role of autoimmunity and neuroinflammation in the pathogenesis of the disease, indicating new target for therapeutic intervention. We mainly focused on the NLRP3 microglial inflammasome as a critical factor in stimulating innate immune responses, thus sustaining chronic inflammation. Additionally, we discussed the involvement of the NLRP3 inflammasome in the gut-brain axis. Direct targeting the NLRP3 inflammasome and the associated receptors could be a potential pharmacological strategy, since its inhibition would selectively reduce AD neuroinflammation.

Microglia in Alzheimer’s Disease

2020 ◽  
Vol 17 (1) ◽  
pp. 29-43 ◽  
Author(s):  
Patrick Süß ◽  
Johannes C.M. Schlachetzki
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Current Knowledge ◽  
Imaging Techniques ◽  
Amyloid Β ◽  
Disease Stage ◽  
Disease Modifying Therapy ◽  
Transcriptomic Signature

: Alzheimer’s Disease (AD) is the most frequent neurodegenerative disorder. Although proteinaceous aggregates of extracellular Amyloid-β (Aβ) and intracellular hyperphosphorylated microtubule- associated tau have long been identified as characteristic neuropathological hallmarks of AD, a disease- modifying therapy against these targets has not been successful. An emerging concept is that microglia, the innate immune cells of the brain, are major players in AD pathogenesis. Microglia are longlived tissue-resident professional phagocytes that survey and rapidly respond to changes in their microenvironment. Subpopulations of microglia cluster around Aβ plaques and adopt a transcriptomic signature specifically linked to neurodegeneration. A plethora of molecules and pathways associated with microglia function and dysfunction has been identified as important players in mediating neurodegeneration. However, whether microglia exert either beneficial or detrimental effects in AD pathology may depend on the disease stage. : In this review, we summarize the current knowledge about the stage-dependent role of microglia in AD, including recent insights from genetic and gene expression profiling studies as well as novel imaging techniques focusing on microglia in human AD pathology and AD mouse models.

AADVAC1, AN ACTIVE IMMUNOTHERAPY FOR ALZHEIMER’S DISEASE AND NON ALZHEIMER TAUOPATHIES: AN OVERVIEW OF PRECLINICAL AND CLINICAL DEVELOPMENT

2018 ◽  
pp. 1-7
Author(s):  
P. Novak ◽  
N. Zilka ◽  
M. Zilkova ◽  
B. Kovacech ◽  
R. Skrabana ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Neurodegenerative Disorder ◽  
Therapeutic Potential ◽  
Phase 1 ◽  
Primary Progressive Aphasia ◽  
Tau Proteins ◽  
Active Immunotherapy ◽  
Tau Pathology

Neurofibrillary tau protein pathology is closely associated with the progression and phenotype of cognitive decline in Alzheimer’s disease and other tauopathies, and a high-priority target for disease-modifying therapies. Herein, we provide an overview of the development of AADvac1, an active immunotherapy against tau pathology, and tau epitopes that are potential targets for immunotherapy. The vaccine leads to the production of antibodies that target conformational epitopes in the microtubule-binding region of tau, with the aim to prevent tau aggregation and spreading of pathology, and promote tau clearance. The therapeutic potential of the vaccine was evaluated in transgenic rats and mice expressing truncated, non mutant tau protein, which faithfully replicate of human tau pathology. Treatment with AADvac1 resulted in reduction of neurofibrillary pathology and insoluble tau in their brains, and amelioration of their deleterious phenotype. The vaccine was highly immunogenic in humans, inducing production of IgG antibodies against the tau peptide in 29/30 treated elderly patients with mild-to-moderate Alzheimer’s. These antibodies were able to recognise insoluble tau proteins in Alzheimer patients’ brains. Treatment with AADvac1 proved to be remarkably safe, with injection site reactions being the only adverse event tied to treatment. AADvac1 is currently being investigated in a phase 2 study in Alzheimer’s disease, and a phase 1 study in non-fluent primary progressive aphasia, a neurodegenerative disorder with a high tau pathology component.

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

Nutrients ◽  
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.

scholarly journals Can blood amyloid levels be used as a biomarker for Alzheimer’s disease?

2021 ◽  
Vol 7 (1) ◽  
pp. 17-25
Author(s):  
Yuan-Han Yang ◽  
Rocksy FV Situmeang ◽  
Paulus Anam Ong
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Outcomes ◽  
Tau Protein ◽  
Clinical Settings ◽  
Access Methods ◽  
Clinical Applicability ◽  
Clinical Stages ◽  
Aging Populations ◽  
Amyloid Aβ

Alzheimer’s disease (AD) increasingly affects society due to aging populations. Even at pre‐clinical stages, earlier and accurate diagnoses are essential for optimal AD management and improved clinical outcomes. Biomarkers such as beta‐amyloid (Aβ) or tau protein in cerebrospinal fluid (CSF) have been used as reliable markers to distinguish AD from non‐AD, and predicting clinical outcomes, to attain these goals. However, given CSF access methods’ invasiveness, these biomarkers are not used extensively in clinical settings. Blood Aβ has been proposed as an alternative biomarker since it is less invasive than CSF; however, sampling heterogeneity has limited its clinical applicability. In this review, we investigated blood Aβ as a biomarker in AD and explored how Aβ can be facilitated as a viable biomarker for successful AD management.

scholarly journals Epigenetics of Alzheimer’s Disease

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 195
Author(s):  
Matea Nikolac Perkovic ◽  
Alja Videtic Paska ◽  
Marcela Konjevod ◽  
Katarina Kouter ◽  
Dubravka Svob Strac ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Posttranslational Modifications ◽  
Neurodegenerative Disorder ◽  
Current Knowledge ◽  
Current Evidence ◽  
Mtdna Copy Number ◽  
Rna Regulation ◽  
The Central Nervous System

There are currently no validated biomarkers which can be used to accurately diagnose Alzheimer’s disease (AD) or to distinguish it from other dementia-causing neuropathologies. Moreover, to date, only symptomatic treatments exist for this progressive neurodegenerative disorder. In the search for new, more reliable biomarkers and potential therapeutic options, epigenetic modifications have emerged as important players in the pathogenesis of AD. The aim of the article was to provide a brief overview of the current knowledge regarding the role of epigenetics (including mitoepigenetics) in AD, and the possibility of applying these advances for future AD therapy. Extensive research has suggested an important role of DNA methylation and hydroxymethylation, histone posttranslational modifications, and non-coding RNA regulation (with the emphasis on microRNAs) in the course and development of AD. Recent studies also indicated mitochondrial DNA (mtDNA) as an interesting biomarker of AD, since dysfunctions in the mitochondria and lower mtDNA copy number have been associated with AD pathophysiology. The current evidence suggests that epigenetic changes can be successfully detected, not only in the central nervous system, but also in the cerebrospinal fluid and on the periphery, contributing further to their potential as both biomarkers and therapeutic targets in AD.

scholarly journals CANINE COGNITIVE DISFUNCTION SYNDROME

2018 ◽  
Vol 15 (2) ◽  
Author(s):  
Dimitris Dimzas ◽  
Nikos Papaioannou ◽  
Magda Tsolaki
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Neurodegenerative Disorder ◽  
Older Age ◽  
Human Aging ◽  
Progressive Dementia

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder that usuallyaffects individuals of an older age. Aged dogs spontaneously develop many featuresof human aging and Alzheimer’s disease (AD) including cognitive decline andneuropathology. AD is accompanied by progressive dementia and the accumulationof senile pla

scholarly journals Tau protein and its role in Alzheimer’s disease physiopathology: a literature review

2021 ◽  
Author(s):  
Larissa Rosa Stork ◽  
Lucca Stephani Ribeiro ◽  
Izabella Savergnini Deprá ◽  
Luísa D’Ávila Camargo ◽  
Maria Angélica Santos Novaes
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
Paired Helical Filaments ◽  
Tau Proteins ◽  
Molecular Aspects ◽  
Cellular Cytoskeleton

Background: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by a double proteinopathy: deposition of amyloid-β into plaques and hyperphosphorylation of Tau protein. Objectives: To understand the genetic and molecular aspects of Tau protein and its relationship with Alzheimer’s disease. Methods: We conducted a systematic literature search using Pubmed/ MEDLINE and ClinicalKey databases, applying the descriptors: “Alzheimer Disease” AND “Tau proteins’’ AND Tauopathies, during July and August of 2020. The inclusion criteria were English and Portuguese articles published between 2015 and 2020, with human limited study and free full text, excluding images, books, clinical tests, and narrative reviews. After analyzing titles and abstracts, we selected 12 articles and included 7 additional studies. Results: Mapt, the encoder gene of Tau, is located in the 17q21.3 locus and presents 16 exons that, when transcripted, originates 12 copies of mRNA by alternative splicing and 6 Tau’s isoforms. Tau is a microtubule-associated protein (MAP) responsible for cellular cytoskeleton stabilization and maintenance, promoting neuronal axonal transport. A kinase-phosphatase imbalance turns Tau hyperphosphorylated, disassociating it from tubulin and grouping it into insoluble paired helical filaments, which originates neurofibrillary tangles. The tauopathy’s progress causes neurotransmitter destabilization and neuronal death, inducing AD symptomatic manifestations. Conclusions: Due to the gradual worsening of the disease to more debilitating stages, studies focused on deepening the knowledge of genetic and molecular aspects of Tau protein are viable and promising alternatives to improve the quality of patient’s lives.

scholarly journals The fluid biomarkers of Alzheimer’s disease

2021 ◽  
Vol 7 (1) ◽  
pp. 1-16
Author(s):  
Qinyu Peng ◽  
Zhentao Zhang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Diagnosis ◽  
Neurodegenerative Disorder ◽  
Future Prospects ◽  
Research Directions ◽  
Disease Modifying Therapies ◽  
Highly Sensitive ◽  
Disease Modifying ◽  
Common Neurodegenerative Disorder

Alzheimer’s disease (AD) is the most common neurodegenerative disorder. However, it still has no available disease‐modifying therapies. Its pathology cascade begins decades before symptomatic presentation. For these reasons, highly sensitive and highly specific fluid biomarkers should be developed for the early diagnosis of AD. In this study, the well‐established and emerging fluid biomarkers of AD are summarized, and recent advances on their role in early diagnosis and progression monitoring as well as their correlations with AD pathology are highlighted. Future prospects and related research directions are also discussed.

scholarly journals Application of CRISPR/Cas9 in Alzheimer’s Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Likui Lu ◽  
Xi Yu ◽  
Yongle Cai ◽  
Miao Sun ◽  
Hao Yang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Complex Disease ◽  
Neurodegenerative Disorder ◽  
Target Therapy ◽  
Abnormal Behavior ◽  
Psychological Suffering ◽  
Pathogenic Genes ◽  
Hyperphosphorylated Tau Protein ◽  
Amyloid Aβ

Alzheimer’s disease (AD) is a progressive and irreversible neurodegenerative disorder clinically characterized by cognitive impairment, abnormal behavior, and social deficits, which is intimately linked with excessive β-amyloid (Aβ) protein deposition along with many other misfolded proteins, neurofibrillary tangles formed by hyperphosphorylated tau protein aggregates, and mitochondrial damage in neurons, leading to neuron loss. Currently, research on the pathological mechanism of AD has been elucidated for decades, still no effective treatment for this complex disease was developed, and the existing therapeutic strategies are extremely erratic, thereby leading to irreversible and progressive cognitive decline in AD patients. Due to gradually mental dyscapacitating of AD patients, AD not only brings serious physical and psychological suffering to patients themselves, but also imposes huge economic burdens on family and society. Accordingly, it is very imperative to recapitulate the progress of gene editing-based precision medicine in the emerging fields. In this review, we will mainly focus on the application of CRISPR/Cas9 technique in the fields of AD research and gene therapy, and summarize the application of CRISPR/Cas9 in the aspects of AD model construction, screening of pathogenic genes, and target therapy. Finally, the development of delivery systems, which is a major challenge that hinders the clinical application of CRISPR/Cas9 technology will also be discussed.

Sign in / Sign up

Export Citation Format

Share Document