Linking the Amyloid, Tau, and Mitochondrial Hypotheses of Alzheimer’s Disease and Identifying Promising Drug Targets

Biomolecules, Journal Year: 2022, Volume and Issue: 12(11), P. 1676 - 1676

Published: Nov. 11, 2022

Damage or loss of brain cells and impaired neurochemistry, neurogenesis, synaptic nonsynaptic plasticity the lead to dementia in neurodegenerative diseases, such as Alzheimer's disease (AD). Injury synapses neurons accumulation extracellular amyloid plaques intracellular neurofibrillary tangles are considered main morphological neuropathological features AD. Age, genetic epigenetic factors, environmental stressors, lifestyle contribute risk AD onset progression. These factors associated with structural functional changes brain, leading cognitive decline. Biomarkers reflect cause specific function, especially pathways neurotransmission, neuroinflammation, bioenergetics, apoptosis, oxidative nitrosative stress. Even initial stages, is Aβ neurotoxicity, mitochondrial dysfunction, tau neurotoxicity. The integrative amyloid-tau-mitochondrial hypothesis assumes that primary neurotoxicity oligomers oligomers, their mutual synergy. For development new efficient drugs, targeting elimination potentiation effects, unwanted protein interactions biomarkers (mainly dysfunction) early stage seems promising.

Language: Английский

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Microglia and Astrocytes in Alzheimer’s Disease: Significance and Summary of Recent Advances

Aging and Disease, Journal Year: 2023, Volume and Issue: unknown, P. 0 - 0

Published: Jan. 1, 2023

Alzheimer’s disease, one of the most common forms dementia, is characterized by a slow progression cognitive impairment and neuronal loss. Currently, approved treatments for AD are hindered various side effects limited efficacy. Despite considerable research, practical have not been developed. Increasing evidence shows that glial cells, especially microglia astrocytes, essential in initiation AD. During progression, activated resident increases ability resting astrocytes to transform into reactive promoting neurodegeneration. Extensive clinical molecular studies show involvement astrocyte-mediated neuroinflammation pathology, indicating may be potential therapeutic targets This review will summarize significant recent advances pathogenesis three parts. First, we typical pathological changes discuss terms function phenotypic changes. Second, describe astrocytes’ physiological role These roles include inflammatory response, “eat me” “don’t eat signals, Aβ seeding, propagation, clearance, synapse loss, synaptic pruning, remyelination, demyelination. Last, pharmacological non-pharmacological therapies targeting We conclude development Therefore, understanding new critical future trials. Moreover, pharmacological, with specific investigating damage repair, promising research direction regarding treatment prevention.

Language: Английский

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Vicious cycle of oxidative stress and neuroinflammation in pathophysiology of chronic vascular encephalopathy

Frontiers in Physiology, Journal Year: 2024, Volume and Issue: 15

Published: Aug. 5, 2024

Chronic vascular encephalopathy (CVE) is a frequent cause of mild cognitive impairment and dementia, which significantly worsens the quality life, especially in elderly population. CVE result chronic cerebral hypoperfusion, characterized by prolonged limited blood flow to brain. This causes insufficient oxygenation brain leading hypoxia. The latter can trigger series events associated with development oxidative/reductive stresses neuroinflammation. Addressing gap knowledge regarding oxidative reductive disorders neuroinflammation give start new directions research context CVE. In this review, we consider hypoxia-induced molecular challenges involved pathophysiology CVE, focusing on stress neuroinflammation, are combined vicious cycle neurodegeneration. We also briefly describe therapeutic approaches treatment outline prospects for use sulforaphane, an isothiocyanate common cruciferous plants, vitamin D break alleviate impairments characteristic patients

Language: Английский

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Bifidobacterium infantis and Bifidobacterium breve Improve Symptomatology and Neuronal Damage in Neurodegenerative Disease: A Systematic Review

Nutrients, Journal Year: 2025, Volume and Issue: 17(3), P. 391 - 391

Published: Jan. 22, 2025

Background/Objectives: This systematic review focused on collecting the most significant findings impact of administration Bifidobacterium infantis (or longum subps. infantis) and breve, alone, in conjunction, or combination with other strains, treatment neurodegenerative diseases including Alzheimer’s disease (AD) Parkinson’s (PD). These are characterized by progressive degeneration neurons, resulting a broad spectrum clinical manifestations. AD is typified decline cognitive abilities, while PD marked motor symptoms associated loss dopamine (DA). Methods: Five different databases, ScienceDirect, Scopus, Wiley, PubMed, Web Science (WoS), were reviewed studies screened for inclusion following criteria: (i) that specifically evaluated use infantis, subsp. breve as therapeutic intervention, either human animal models, context diseases; (ii) required to address one more pathologies examined this article, included, but not limited to, neurodegeneration, disease, oxidative stress; (iii) full text was accessible online; (iv) article written English. Results: The data suggest these probiotics have neuroprotective effects may delay progression. Conclusions: study provides updated insights into strains like PD, main limitation being number trials available.

Language: Английский

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Whole genome methylation sequencing in blood from persons with mild cognitive impairment and dementia due to Alzheimer's disease identifies cognitive status

Alzheimer s & Dementia, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Abstract INTRODUCTION Whole genome methylation sequencing (WGMS) in blood identifies differential DNA persons with late‐onset dementia due to Alzheimer's disease (AD) but has not been tested mild cognitive impairment (MCI). METHODS We used WGMS compare levels at 25,244,219 CpG loci 382 samples from 99 MCI, 109 AD, and 174 who are cognitively unimpaired (CU). RESULTS identified 9756 differentially methylated positions (DMPs) including 1743 genes encoding proteins biological pathways related synapse organization, dendrite development, ion transport. A total of 447 DMPs exhibit progressively increasing or decreasing among CU, AD that correspond status. DISCUSSION known newly detected MCI support can distinguish Highlights (MCI), disease, were analyzed. Nine thousand seven hundred fifty‐six MCI. One forty‐three comprise one more Fifty‐eight 392 shared the three pairwise comparisons. Four forty‐seven progressive changes

Language: Английский

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Integrated Multi-Omics Analyses of Synaptosomes Revealed Synapse-Centered Novel Targets in Alzheimer's Disease

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 13, 2025

Synapse dysfunction is an early event in Alzheimer's disease (AD) caused by various factors such as Amyloid beta, p-tau, inflammation, and aging. However, the exact molecular mechanism of synapse AD largely unknown. To understand this, we comprehensively analyzed synaptosome fraction postmortem brain samples from patients cognitively normal individuals. We conducted high-throughput transcriptomic analyses to identify changes microRNA (miRNA) mRNA levels synaptosomes extracted brains both unaffected individuals those with (AD). Additionally, performed mass spectrometry analysis synaptosomal proteins same sample group. These revealed significant differences miRNAs, mRNAs, between groups. further pathways or molecules involved, used integrated omics approach studied interactions deregulated control group, which demonstrated impact miRNAs on their target mRNAs proteins. Furthermore, DIABLO highlighted complex relationships that could be key understanding pathophysiology AD. Our study identified synapse-centered novel candidates critical restoring

Language: Английский

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Synapse vulnerability and resilience underlying Alzheimer’s disease

EBioMedicine, Journal Year: 2025, Volume and Issue: 112, P. 105557 - 105557

Published: Jan. 31, 2025

Synapse preservation is key for healthy cognitive ageing, and synapse loss represents a critical anatomical basis of dysfunction in Alzheimer's disease (AD), predicting dementia onset, severity, progression. viewed as primary pathologic event, preceding neuronal brain atrophy AD. Synapses may, therefore, represent one the earliest clinically most meaningful targets neuropathologic processes driving AD dementia. The highly selective particularly vulnerable synapses while leaving others, termed resilient, largely unaffected. Yet, anatomic molecular hallmarks resilient populations their association with changes (e.g. amyloid-β plaques tau tangles) memory remain poorly understood. Characterising selectively may be to understanding mechanisms versus enable development robust biomarkers disease-modifying therapies

Language: Английский

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Astaxanthin nanoemulsion improves cognitive function and synaptic integrity in Streptozotocin-induced Alzheimer’s disease model

Metabolic Brain Disease, Journal Year: 2025, Volume and Issue: 40(3)

Published: March 6, 2025

Language: Английский

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Proteomic analysis identifies HSP90AA1, PTK2B, and ANXA2 in the human entorhinal cortex in Alzheimer's disease: Potential role in synaptic homeostasis and Aβ pathology through microglial and astroglial cells

Brain Pathology, Journal Year: 2024, Volume and Issue: 34(4)

Published: Jan. 22, 2024

Abstract Alzheimer's disease (AD), the most prevalent neurodegenerative disorder worldwide, is clinically characterized by cognitive deficits. Neuropathologically, AD brains accumulate deposits of amyloid‐β (Aβ) and tau proteins. Furthermore, these misfolded proteins can propagate from cell to in a prion‐like manner induce native become pathological. The entorhinal cortex (EC) among earliest areas affected accumulation along with volume reduction neurodegeneration. Neuron–glia interactions have recently come into focus; however, role microglia astroglia pathogenesis remains unclear. Proteomic approaches allow determination changes proteome better understand pathology underlying AD. Bioinformatic analysis proteomic data was performed compare ECs non‐AD human brain tissue. To validate results, western blot, immunofluorescence, confocal studies were carried out. findings revealed that disturbed signaling pathway synaptogenesis. Because their involvement synapse function, relationship Aβ analysis, three selected for in‐depth study: HSP90AA1, PTK2B, ANXA2. All showed colocalization neurons and/or pathological In particular, ANXA2, which overexpressed AD, colocalized amoeboid microglial cells plaques surrounded astrocytes. Taken together, evidence suggests unbalanced expression ANXA2 may play significant synaptic homeostasis through astroglial EC

Language: Английский

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Monitoring synaptic pathology in Alzheimer’s disease through fluid and PET imaging biomarkers: a comprehensive review and future perspectives

Molecular Psychiatry, Journal Year: 2024, Volume and Issue: 29(3), P. 847 - 857

Published: Jan. 16, 2024

Language: Английский

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