Cited by 1,740Alzheimer's disease research and treatmentsAutophagy in Disease and TherapyNeuroinflammation and Neurodegeneration Mechanisms

Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease

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Fang, Evandro F., Hou, Yujun, Palikaras, Konstantinos, Adriaanse, Bryan A., Kerr, Jesse S., Yang, Beimeng, Lautrup, Sofie, Hasan-Olive, Md Mahdi +12 more·2019·Nature Neuroscience

Abstract

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].”
  • 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.”
  • 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).”

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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.
Venue
Nature Neuroscience
Published
2019-02-11
Volume
22
Issue
3
Pages
401-412
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
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
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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