Autophagy and Cellular Senescence in Alzheimer's Disease: Key Drivers of Neurodegeneration

Hussain, MS; Agrawal, N; Ilma, B; M M, R; Nayak, PP; Kaur, M; Khachi, A; Goyal, K; Rekha, A; Gupta, S; Gupta, G; Dua, K

Autophagy and Cellular Senescence in Alzheimer's Disease: Key Drivers of Neurodegeneration

Hussain, MS Agrawal, N Ilma, B M M, R Nayak, PP Kaur, M Khachi, A Goyal, K Rekha, A Gupta, S Gupta, G Dua, K

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Publisher:: Wiley
Publication Type:: Journal Article
Citation:: CNS Neuroscience & Therapeutics, 2025, 31, (7)
Issue Date:: 2025-07

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Field	Value	Language
dc.contributor.author	Hussain, MS
dc.contributor.author	Agrawal, N
dc.contributor.author	Ilma, B
dc.contributor.author	M M, R
dc.contributor.author	Nayak, PP
dc.contributor.author	Kaur, M
dc.contributor.author	Khachi, A
dc.contributor.author	Goyal, K
dc.contributor.author	Rekha, A
dc.contributor.author	Gupta, S
dc.contributor.author	Gupta, G
dc.contributor.author	Dua, K https://orcid.org/0000-0002-7507-1159
dc.date.accessioned	2025-07-26T15:29:56Z
dc.date.available	2025-07-26T15:29:56Z
dc.date.issued	2025-07
dc.identifier.citation	CNS Neuroscience & Therapeutics, 2025, 31, (7)
dc.identifier.issn	1755-5930
dc.identifier.issn	1755-5949
dc.identifier.uri	http://hdl.handle.net/10453/188852
dc.description.abstract	<jats:title>ABSTRACT</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Alzheimer's disease (AD) is a progressive neurodegenerative disorder in the elderly, characterized by extracellular amyloid β‑ (Aβ) plaque deposition and intracellular neurofibrillary tangles (NFTs). Impaired autophagy, the cellular pathway for degrading damaged organelles and misfolded proteins, and cellular senescence, permanent cell cycle arrest with proinflammatory secretions, have emerged as key contributors to AD pathogenesis.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We performed a narrative review of recent mechanistic and preclinical studies investigating (1) autophagic flux and its role in Aβ and tau clearance; (2) the accumulation and secretory phenotype of senescent cells in the aging brain; (3) interactions between autophagy impairment and senescence; and (4) the efficacy of autophagy enhancers (e.g., rapamycin and metformin) and senolytic agents in rodent models of AD.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Defective autophagosome–lysosome fusion in AD causes autophagic vacuole buildup with amyloid precursor protein and β‑secretase, boosting Aβ generation and hindering tau clearance, promoting neurofibrillary tangles. In AD models, senescent neurons and microglia release pro‑inflammatory cytokines (SASP), fueling neuroinflammation and synaptic dysfunction. Decline in autophagy induces senescence and blocks clearance in a vicious cycle. Rapamycin and metformin restore autophagic flux, reduce Aβ and tau pathologies, and improve memory. Senolytics clear senescent cells, reduce inflammation, and rescue cognition.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Dysregulated autophagy and cellular senescence interact to drive the progression of AD. Targeting these pathways with autophagy‐boosting drugs and senolytic agents holds promise for disease‐modifying therapies aimed at halting or reversing neurodegeneration in Alzheimer's disease.</jats:p></jats:sec>
dc.language	en
dc.publisher	Wiley
dc.relation.ispartof	CNS Neuroscience & Therapeutics
dc.relation.isbasedon	10.1111/cns.70503
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	1109 Neurosciences, 1115 Pharmacology and Pharmaceutical Sciences
dc.subject.classification	Pharmacology & Pharmacy
dc.subject.classification	3209 Neurosciences
dc.subject.classification	3214 Pharmacology and pharmaceutical sciences
dc.title	Autophagy and Cellular Senescence in Alzheimer's Disease: Key Drivers of Neurodegeneration
dc.type	Journal Article
utslib.citation.volume	31
utslib.for	1109 Neurosciences
utslib.for	1115 Pharmacology and Pharmaceutical Sciences
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Health
pubs.organisational-group	University of Technology Sydney/UTS Groups
pubs.organisational-group	University of Technology Sydney/UTS Groups/Centre for Inflammation (CFI)
pubs.organisational-group	University of Technology Sydney/UTS Groups/Centre for Inflammation (CFI)/Centre for Inflammation (CFI) Associate Members
pubs.organisational-group	University of Technology Sydney/UTS Groups/Australian Research Consortium in Complementary and Integrative Medicine (ARCCIM)
pubs.organisational-group	University of Technology Sydney/UTS Groups/Stroke Research Collaborative
utslib.copyright.status	open_access	*
dc.rights.license	This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/
dc.date.updated	2025-07-26T15:29:55Z
pubs.issue	7
pubs.publication-status	Published
pubs.volume	31
utslib.citation.issue	7

Abstract:

ABSTRACTBackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder in the elderly, characterized by extracellular amyloid β‑ (Aβ) plaque deposition and intracellular neurofibrillary tangles (NFTs). Impaired autophagy, the cellular pathway for degrading damaged organelles and misfolded proteins, and cellular senescence, permanent cell cycle arrest with proinflammatory secretions, have emerged as key contributors to AD pathogenesis.MethodsWe performed a narrative review of recent mechanistic and preclinical studies investigating (1) autophagic flux and its role in Aβ and tau clearance; (2) the accumulation and secretory phenotype of senescent cells in the aging brain; (3) interactions between autophagy impairment and senescence; and (4) the efficacy of autophagy enhancers (e.g., rapamycin and metformin) and senolytic agents in rodent models of AD.ResultsDefective autophagosome–lysosome fusion in AD causes autophagic vacuole buildup with amyloid precursor protein and β‑secretase, boosting Aβ generation and hindering tau clearance, promoting neurofibrillary tangles. In AD models, senescent neurons and microglia release pro‑inflammatory cytokines (SASP), fueling neuroinflammation and synaptic dysfunction. Decline in autophagy induces senescence and blocks clearance in a vicious cycle. Rapamycin and metformin restore autophagic flux, reduce Aβ and tau pathologies, and improve memory. Senolytics clear senescent cells, reduce inflammation, and rescue cognition.ConclusionDysregulated autophagy and cellular senescence interact to drive the progression of AD. Targeting these pathways with autophagy‐boosting drugs and senolytic agents holds promise for disease‐modifying therapies aimed at halting or reversing neurodegeneration in Alzheimer's disease.

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http://hdl.handle.net/10453/188852