New Pathways Identify Novel Drug Targets for the Prevention and Treatment of Alzheimer’s Disease DOI Open Access
Botond Penke,

Mária Szűcs,

Ferenc Bogár

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(6), P. 5383 - 5383

Published: March 11, 2023

Alzheimer’s disease (AD) is an incurable, progressive neurodegenerative disorder. AD a complex and multifactorial that responsible for 60–80% of dementia cases. Aging, genetic factors, epigenetic changes are the main risk factors AD. Two aggregation-prone proteins play decisive role in pathogenesis: β-amyloid (Aβ) hyperphosphorylated tau (pTau). Both them form deposits diffusible toxic aggregates brain. These biomarkers Different hypotheses have tried to explain pathogenesis served as platforms drug research. Experiments demonstrated both Aβ pTau might start processes necessary cognitive decline. The two pathologies act synergy. Inhibition formation has been old target. Recently, successful clearance by monoclonal antibodies raised new hopes treatments if detected at early stages. More recently, novel targets, e.g., improvements amyloid from brain, application small heat shock (Hsps), modulation chronic neuroinflammation different receptor ligands, microglial phagocytosis, increase myelination revealed

Language: Английский

The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics DOI
Eric Karran, Bart De Strooper

Nature Reviews Drug Discovery, Journal Year: 2022, Volume and Issue: 21(4), P. 306 - 318

Published: Feb. 17, 2022

Language: Английский

Citations

487
Hypothesis: Tau pathology is an initiating factor in sporadic Alzheimer's disease DOI Creative Commons
Amy F.T. Arnsten, Dibyadeep Datta, Kelly Del Tredici

et al.

Alzheimer s & Dementia, Journal Year: 2020, Volume and Issue: 17(1), P. 115 - 124

Published: Oct. 19, 2020

Abstract The etiology of the common, sporadic form Alzheimer's disease (sAD) is unknown. We hypothesize that tau pathology within select projection neurons with susceptible microenvironments can initiate sAD. This postulate rests on extensive data demonstrating in human brains appears about a decade before formation Aβ plaques (Aβps), especially targeting glutamate association cortex. Data from aging rhesus monkeys show abnormal phosphorylation vulnerable neurons, associated calcium dysregulation. Abnormally phosphorylated (pTau) microtubules traps APP‐containing endosomes, which increase production. As oligomers tau, this would drive vicious cycles leading to sAD over long lifespan, genetic and environmental factors may accelerate pathological events. hypothesis could be testable aged monkey cortex naturally expresses characteristics capable promoting sustaining

Language: Английский

Citations

272
Synaptic degeneration in Alzheimer disease DOI
Makis Tzioras, Robert I. McGeachan, Claire S. Durrant

et al.

Nature Reviews Neurology, Journal Year: 2022, Volume and Issue: 19(1), P. 19 - 38

Published: Dec. 13, 2022

Language: Английский

Citations

250
Alzheimer's‐like signaling in brains of COVID‐19 patients DOI Creative Commons
Steve Reiken, Leah Sittenfeld, Haikel Dridi

et al.

Alzheimer s & Dementia, Journal Year: 2022, Volume and Issue: 18(5), P. 955 - 965

Published: Feb. 3, 2022

The mechanisms that lead to cognitive impairment associated with COVID-19 are not well understood.Brain lysates from control and patients were analyzed for oxidative stress inflammatory signaling pathway markers, measurements of Alzheimer's disease (AD)-linked biochemistry. Post-translational modifications the ryanodine receptor/calcium (Ca2+ ) release channels (RyR) on endoplasmic reticuli (ER), known be linked AD, also measured by co-immunoprecipitation/immunoblotting brain lysates.We provide evidence linking SARS-CoV-2 infection activation TGF-β overload. neuropathological pathways causing tau hyperphosphorylation typically AD shown activated in patients. RyR2 brains demonstrated a "leaky" phenotype, which can promote behavioral defects.COVID-19 neuropathology includes AD-like features leaky could therapeutic target amelioration some defects long COVID.

Language: Английский

Citations

156
APOE in the bullseye of neurodegenerative diseases: impact of the APOE genotype in Alzheimer’s disease pathology and brain diseases DOI Creative Commons
Rosalía Fernández‐Calle, Sabine C. Konings, Javier Frontiñán-Rubio

et al.

Molecular Neurodegeneration, Journal Year: 2022, Volume and Issue: 17(1)

Published: Sept. 24, 2022

Abstract ApoE is the major lipid and cholesterol carrier in CNS. There are three human polymorphisms, apoE2, apoE3, apoE4, genetic expression of APOE4 one most influential risk factors for development late-onset Alzheimer's disease (AD). Neuroinflammation has become third hallmark AD, together with Amyloid-β plaques neurofibrillary tangles hyperphosphorylated aggregated tau protein. This review aims to broadly extensively describe differential aspects concerning apoE. Starting from evolution apoE how APOE's single-nucleotide polymorphisms affect its structure, function, involvement during health disease. reflects on impact critical AD pathology, such as neuroinflammatory response, particularly effect APOE astrocytic microglial function dynamics, synaptic amyloid-β load, autophagy, cell–cell communication. We discuss affecting pathology combined genotype, sex, age, diet, physical exercise, current therapies clinical trials field. The genotype other neurodegenerative diseases characterized by overt inflammation, e.g., alpha- synucleinopathies Parkinson's disease, traumatic brain injury, stroke, amyotrophic lateral sclerosis, multiple also addressed. Therefore, this gathers relevant findings related up date implications CNS pathologies provide a deeper understanding knowledge

Language: Английский

Citations

142
Microglia and Alzheimer’s Disease DOI Open Access
Stefania Merighi,

Manuela Nigro,

Alessia Travagli

et al.

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(21), P. 12990 - 12990

Published: Oct. 27, 2022

There is a huge need for novel therapeutic and preventative approaches to Alzheimer’s disease (AD) neuroinflammation seems be one of the most fascinating solutions. The primary cell type that performs immunosurveillance helps clear out unwanted chemicals from brain microglia. Microglia work reestablish efficiency stop further degeneration in early stages AD but mainly fail illness’s later phases. This may caused by number reasons, e.g., protracted exposure cytokines induce inflammation an inappropriate accumulation amyloid beta (Aβ) peptide. Extracellular and/or intraneuronal phosphorylated tau can both activate activation TLRs scavenger receptors, inducing numerous inflammatory pathways, including NF-kB, JAK-STAT, NLRP3 inflammasome, facilitates microglial phagocytosis response these mediators. Aβ/tau are taken up microglia, their removal extracellular space also have protective effects, if illness worsens, environment constantly inflamed overexposed oxidative might encourage continuous activation, which lead neuroinflammation, stress, iron overload, neurotoxicity. complexity diversity roles microglia play health necessitate urgent development new biomarkers identify activity different It imperative comprehend intricate mechanisms result impairment develop immunomodulating therapies primarily attempt recover physiological role allowing them carry core function protection.

Language: Английский

Citations

114
Signal pathways in the treatment of Alzheimer’s disease with traditional Chinese medicine DOI Open Access

Min-Rui Ding,

Yan-Jie Qu,

Bing Hu

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2022, Volume and Issue: 152, P. 113208 - 113208

Published: May 31, 2022

This study aimed to reveal the classical signal pathways and important potential targets of traditional Chinese medicine (TCM) for treating Alzheimer's disease (AD), provide support further investigation on TCM its active ingredients.Literature survey was conducted using PubMed, Web Science, Google Scholar, CNKI, other databases, with "Alzheimer's disease," "traditional medicine," "medicinal herb," "Chinese "natural plant" as primary keywords.TCM could modulate related AD pathological progression, including NF-κB, Nrf2, JAK/STAT, ubiquitin-proteasome pathway, autophagy-lysosome pathway-related AMPK/mTOR, GSK-3/mTOR, PI3K/Akt/mTOR, well SIRT1 PPARα pathway. It regulate crosstalk between through a multitarget, thus maintaining chronic inflammatory interaction balance, inhibiting oxidative stress damage, regulating system function, modulating autophagy, eventually improving cognitive impairment in patients AD.TCM be multilevel, multitargeted, multifaceted prevent treat AD. In-depth research prevention treatment new ideas exploring pathogenesis developing anti-AD drugs.

Language: Английский

Citations

83
Exercise suppresses neuroinflammation for alleviating Alzheimer’s disease DOI Creative Commons
Minghui Wang, Hu Zhang, Jiling Liang

et al.

Journal of Neuroinflammation, Journal Year: 2023, Volume and Issue: 20(1)

Published: March 19, 2023

Abstract Alzheimer’s disease (AD) is a chronic neurodegenerative disease, with the characteristics of neurofibrillary tangle (NFT) and senile plaque (SP) formation. Although great progresses have been made in clinical trials based on relevant hypotheses, these studies are also accompanied by emergence toxic side effects, it an urgent task to explore underlying mechanisms for benefits prevent treat AD. Herein, animal experiments few trials, neuroinflammation AD characterized long-term activation pro-inflammatory microglia NOD-, LRR- pyrin domain-containing protein 3 (NLRP3) inflammasomes. Damaged signals from periphery within brain continuously activate microglia, thus resulting constant source inflammatory responses. The response exacerbates endoplasmic reticulum oxidative stress which triggers microglia-dependent immune responses, ultimately leading occurrence deterioration In this review, we systematically summarized sorted out that exercise ameliorates directly indirectly regulating central nervous system promoting hippocampal neurogenesis provide new direction exploring activity

Language: Английский

Citations

83
Innate immune activation in neurodegenerative diseases DOI
Sergio Castro‐Gomez, Michael T. Heneka

Immunity, Journal Year: 2024, Volume and Issue: 57(4), P. 790 - 814

Published: April 1, 2024

Language: Английский

Citations

21
Review on anti-alzheimer drug development: approaches, challenges and perspectives DOI Creative Commons
Abdallah E. Abdallah

RSC Advances, Journal Year: 2024, Volume and Issue: 14(16), P. 11057 - 11088

Published: Jan. 1, 2024

Alzheimer has many crucial factors that should be considered in order to get better results from clinical trials. Benzimidazole and its isosteres represent significant scaffolds for designing potential multi-target anti-alzheimer molecules.

Language: Английский

Citations

19