Defective mitophagy in Alzheimer’s disease
Open accessAbstract
Alzheimer's disease (AD) is a progressive, mental illness without cure. Several years of intense research on postmortem AD brains, cell and mouse models of AD have revealed that multiple cellular changes are involved in the disease process, including mitochondrial abnormalities, synaptic damage, and glial/astrocytic activation, in addition to age-dependent accumulation of amyloid beta (Aβ) and hyperphosphorylated tau (p-tau). Synaptic damage and mitochondrial dysfunction are early cellular changes in the disease process. Healthy and functionally active mitochondria are essential for cellular functioning. Dysfunctional mitochondria play a central role in aging and AD. Mitophagy is a cellular process whereby damaged mitochondria are selectively removed from cell and mitochondrial quality and biogenesis. Mitophagy impairments cause the progressive accumulation of defective organelle and damaged mitochondria in cells. In AD, increased levels of Aβ and p-tau can induce reactive oxygen species (ROS) production, causing excessive fragmentation of mitochondria and promoting defective mitophagy. The current article discusses the latest developments of mitochondrial research and also highlights multiple types of mitophagy, including Aβ and p-tau-induced mitophagy, stress-induced mitophagy, receptor-mediated mitophagy, ubiquitin mediated mitophagy and basal mitophagy. This article also discusses the physiological states of mitochondria, including fission-fusion balance, Ca 2+ transport, and mitochondrial transport in normal and diseased conditions. Our article summarizes current therapeutic interventions, like chemical or natural mitophagy enhancers, that influence mitophagy in AD. Our article discusses whether a partial reduction of Drp1 can be a mitophagy enhancer and a therapeutic target for mitophagy in AD and other neurological diseases.
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Disruption of autophagic flux and failure of autophagosomes to fuse with lysosomes result in accumulation of vesicles observed in dystrophic neurites and cell bodies in tauopathy models.
“The disruption of the autophagic flux and the failure of autophagosomes to fuse with lysosomes result in the accumulation of vesicles, which can be observed in dystrophic neurites and cell bodies in tauopathy models [27,28,29].”
From Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review (2024) · cites this paper as [27]
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References 203 · Cited by 367
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- Authors
- Pradeepkiran, J. A., & Reddy, P. H.
- Affiliations
- Texas Tech University Health Sciences Center (US)
- Texas Tech University (US)
- Corresponding author
- Reddy, P. Hemachandra
- Venue
- Ageing Research Reviews
- Publisher
- Elsevier BV
- Published
- 2020-12
- Volume
- 64
- Pages
- 101191
- ISSN
- 1568-1637 (ISSN-L)
- PMC
- PMC7710581
- OpenAlex
- W3091354748
- Cited by
- 367
- References
- 203
- Citations by year
- 2026: 63 · 2025: 70 · 2024: 81 · 2023: 63 · 2022: 49 · 2021: 39 · 2020: 2
- FWCI
- 5.61
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Ageing Research Reviews (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (AG042178, AG069333, AG047812, AG060767, NS105473)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- Alzheimer's disease, mitophagy, mitochondrial dysfunction, amyloid-beta, hyperphosphorylated tau, Drp1, autophagy, synaptic dysfunction, calcium transport, mitochondrial transport, reactive oxygen species
- MeSH terms
- Alzheimer Disease, Animals, Disease Models, Animal, Mitochondria, Amyloid beta-Peptides, Mice, Mitophagy
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