Autophagy and Cellular Senescence in Alzheimer's Disease: Key Drivers of Neurodegeneration
Md Sadique Hussain,
Neetu Agrawal,
Baby Ilma,
Rekha M M,
Priya Priyadarshini Nayak,
Mandeep Kaur,
Anil Khachi,
Kavita Goyal,
Arcot Rekha,
Saurabh Gupta,
Gaurav Gupta,
Kamal Dua,
Md Sadique Hussain
Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India
Search for more papers by this authorNeetu Agrawal
Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India
Search for more papers by this authorBaby Ilma
Sharda School of Pharmacy, Sharda University, Greater Noida, Uttar Pradesh, India
Search for more papers by this authorRekha M M
Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India
Search for more papers by this authorPriya Priyadarshini Nayak
Department of Medical Oncology, IMS and SUM Hospital, Siksha ‘O’ Anusandhan (Deemed to Be University), Bhubaneswar, Odisha, India
Search for more papers by this authorMandeep Kaur
Department of Allied Healthcare and Sciences, Vivekananda Global University, Jaipur, Rajasthan, India
Search for more papers by this authorAnil Khachi
Department of Applied Sciences, Chandigarh Engineering College, Chandigarh Group of Colleges-Jhanjeri, Mohali, Punjab, India
Search for more papers by this authorKavita Goyal
Department of Biotechnology, Graphic Era (Deemed to Be University), Dehradun, India
Search for more papers by this authorArcot Rekha
Dr.D.Y.Patil Medical College, Hospital and Research Centre, Pimpri, Pune, India
Search for more papers by this authorSaurabh Gupta
Department of Pharmacology, Chameli Devi Institute of Pharmacy, Indore, Madhya Pradesh, India
Search for more papers by this authorCorresponding Author
Gaurav Gupta
Centre for Research Impact & Outcome, Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, UAE
Correspondence:
Gaurav Gupta ([email protected])
Kamal Dua ([email protected])
Search for more papers by this authorCorresponding Author
Kamal Dua
Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney, New South Wales, Australia
Woolcock Institute of Medical Research, Macquarie University, Sydney, New South Wales, Australia
Correspondence:
Gaurav Gupta ([email protected])
Kamal Dua ([email protected])
Search for more papers by this authorMd Sadique Hussain,
Neetu Agrawal,
Baby Ilma,
Rekha M M,
Priya Priyadarshini Nayak,
Mandeep Kaur,
Anil Khachi,
Kavita Goyal,
Arcot Rekha,
Saurabh Gupta,
Gaurav Gupta,
Kamal Dua,
Md Sadique Hussain
Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India
Search for more papers by this authorNeetu Agrawal
Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India
Search for more papers by this authorBaby Ilma
Sharda School of Pharmacy, Sharda University, Greater Noida, Uttar Pradesh, India
Search for more papers by this authorRekha M M
Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India
Search for more papers by this authorPriya Priyadarshini Nayak
Department of Medical Oncology, IMS and SUM Hospital, Siksha ‘O’ Anusandhan (Deemed to Be University), Bhubaneswar, Odisha, India
Search for more papers by this authorMandeep Kaur
Department of Allied Healthcare and Sciences, Vivekananda Global University, Jaipur, Rajasthan, India
Search for more papers by this authorAnil Khachi
Department of Applied Sciences, Chandigarh Engineering College, Chandigarh Group of Colleges-Jhanjeri, Mohali, Punjab, India
Search for more papers by this authorKavita Goyal
Department of Biotechnology, Graphic Era (Deemed to Be University), Dehradun, India
Search for more papers by this authorArcot Rekha
Dr.D.Y.Patil Medical College, Hospital and Research Centre, Pimpri, Pune, India
Search for more papers by this authorSaurabh Gupta
Department of Pharmacology, Chameli Devi Institute of Pharmacy, Indore, Madhya Pradesh, India
Search for more papers by this authorCorresponding Author
Gaurav Gupta
Centre for Research Impact & Outcome, Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, UAE
Correspondence:
Gaurav Gupta ([email protected])
Kamal Dua ([email protected])
Search for more papers by this authorCorresponding Author
Kamal Dua
Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney, New South Wales, Australia
Woolcock Institute of Medical Research, Macquarie University, Sydney, New South Wales, Australia
Correspondence:
Gaurav Gupta ([email protected])
Kamal Dua ([email protected])
Search for more papers by this authorFirst published: 23 July 2025
Funding: The authors received no specific funding for this work.
ABSTRACT
Background
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.
Methods
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.
Results
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.
Conclusion
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.
Conflicts of Interest
The authors declare no conflicts of interest.
Open Research
Data Availability Statement
Data sharing is not applicable to this article as no new data were created or analyzed in this study.
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