Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease
Open accessAbstract
Accumulation of damaged mitochondria is a hallmark of aging and age-related neurodegeneration, including Alzheimer's disease (AD). The molecular mechanisms of impaired mitochondrial homeostasis in AD are being investigated. Here we provide evidence that mitophagy is impaired in the hippocampus of AD patients, in induced pluripotent stem cell-derived human AD neurons, and in animal AD models. In both amyloid-β (Aβ) and tau Caenorhabditis elegans models of AD, mitophagy stimulation (through NAD+ supplementation, urolithin A, and actinonin) reverses memory impairment through PINK-1 (PTEN-induced kinase-1)-, PDR-1 (Parkinson's disease-related-1; parkin)-, or DCT-1 (DAF-16/FOXO-controlled germline-tumor affecting-1)-dependent pathways. Mitophagy diminishes insoluble Aβ 1-42 and Aβ 1-40 and prevents cognitive impairment in an APP/PS1 mouse model through microglial phagocytosis of extracellular Aβ plaques and suppression of neuroinflammation. Mitophagy enhancement abolishes AD-related tau hyperphosphorylation in human neuronal cells and reverses memory impairment in transgenic tau nematodes and mice. Our findings suggest that impaired removal of defective mitochondria is a pivotal event in AD pathogenesis and that mitophagy represents a potential therapeutic intervention.
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Impairment of mitophagic activity can induce synaptic dysfunction and trigger cognitive deficits by enhancing Aβ and tau accumulation, and stimulation of mitophagy reverses memory loss in nematode and mouse models of AD.
“A recent study reports that impairment of mitophagic activity can induce synaptic dysfunction and trigger cognitive deficits by enhancing Aβ and tau accumulation, and stimulation of mitophagy reverses memory loss in nematode and mouse models of AD [519].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [519]
NAD+ precursors NR and NMN improve neuronal cell health, memory and cognitive function in rat and mouse models of Alzheimer disease, and show neuroprotective properties in Drosophila models of Parkinson disease and mouse models of ALS.
“the NAD+ precursors NR and NMN improve neuronal cell health, memory and cognitive function in rat and mouse models of Alzheimer disease136,161,175–180, and also showed neuroprotective properties in Drosophila melanogaster models of Parkinson disease181,182 and in mouse models of ALS139.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [180]
Hippocampal Fndc5 expression is significantly reduced at six months of age in APP/PS1 mice compared with WT littermates.
“Hippocampal Fndc5 gene expression is significantly reduced at six months of age in the well-established transgenic AD mouse model APP/PS1 (APPswe,PSEN1dE9)51,52 compared to WT littermates (Fig. 6a).”
From Exercise hormone irisin is a critical regulator of cognitive function (2021) · cites this paper as [52]
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Urolithin A improves Alzheimer's disease cognition and restores mitophagy and lysosomal functions
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Mitophagy and cGAS–STING crosstalk in neuroinflammation
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Microglial mitophagy mitigates neuroinflammation in Alzheimer's disease
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Self-citationCGAS is a micronucleophagy receptor for the clearance of micronuclei
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An Unbalanced Synaptic Transmission: Cause or Consequence of the Amyloid Oligomers Neurotoxicity?
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DNA Damage-Induced Neurodegeneration in Accelerated Ageing and Alzheimer’s Disease
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Self-citationThe contribution of altered neuronal autophagy to neurodegeneration
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Accumulation of APP-CTF induces mitophagy dysfunction in the iNSCs model of Alzheimer’s disease
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“As expected, mitophagy is widely impaired in respective models as well as in the brains of AD and PD patients, while the selective pharmacological enhancement of mitophagy can reverse several other pathological aspects, such as the generation of insoluble Aβ, Tau hyperphosphorylation, neuroinflammation, neuronal atrop…”
BackgroundMitochondria and Cellular Redox State on the Route from Ageing to Alzheimer's Disease
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Streptozotocin-induced astrocyte mitochondrial dysfunction is ameliorated by FTO inhibitor MO-I-500
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The link between Mitochondria and Sarcopenia
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Preserved autophagy in cognitively intact non‐demented individuals with Alzheimer's neuropathology
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Pathogenesis, Animal Models, and Drug Discovery of Alzheimer’s Disease
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Alterations of lipid‐mediated mitophagy result in aging‐dependent sensorimotor defects
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- Authors
- Fang, E. F., Hou, Y., Palikaras, K., Adriaanse, B. A., Kerr, J. S., Yang, B., Lautrup, S., Hasan-Olive, M. M., Caponio, D., Dan, X., Rocktäschel, P., Croteau, D. L., Akbari, M., Greig, N. H., Fladby, T., Nilsen, H., Cader, M. Z., Mattson, M. P., Tavernarakis, N., & Bohr, V. A.
- Affiliations
- National Institutes of Health (US)
- National Institute on Aging (US)
- University of Crete (GR)
- University of Oxford (GB)
- University of Oslo (NO)
- University of Copenhagen (DK)
- Corresponding author
- Fang, Evandro F.
- Bohr, Vilhelm A.
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2019-02-11
- Volume
- 22
- Issue
- 3
- Pages
- 401-412
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC6693625
- OpenAlex
- W2911248861
- Cited by
- 1,740
- References
- 67
- Citations by year
- 2026: 230 · 2025: 268 · 2024: 272 · 2023: 243 · 2022: 241 · 2021: 235 · 2020: 181 · 2019: 70
- FWCI
- 124.60
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- NORA - Norwegian Open Research Archives (submittedVersion, other-oa)
- Funders
- National Institutes of Health
- Medical Research Council (1826429, MC_PC_16034, 1826685)
- National Institute on Aging (Z01AG000726)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- mitophagy, Alzheimer's disease, amyloid-beta, tau hyperphosphorylation, mitochondrial homeostasis, PINK1, Parkin, NAD+ supplementation, urolithin A, actinonin, microglial phagocytosis, neuroinflammation, memory impairment, APP/PS1 mice, cognitive impairment, therapeutic interventions
- MeSH terms
- Alzheimer Disease, Animals, Disease Models, Animal, Female, Hippocampus, Male, Memory, Neurons, Amyloid beta-Peptides, Caenorhabditis elegans, Animals, Genetically Modified, Mice, Induced Pluripotent Stem Cells, Neural Stem Cells, Mitophagy
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