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

Journal article

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.

Authors: Fang, EF; Hou, Y; Palikaras, K; Adriaanse, BA; Kerr, JS

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Nature Neuroscience
• Volume: 22
• Issue: 3
• Pages: 401-412
• Place of publication: United States
• Publication date: 2019-02-11
• Acceptance date: 2018-12-17
• DOI: 10.1038/s41593-018-0332-9
• EISSN: 1546-1726
• ISSN: 1097-6256
• Pmid: 30742114
• Language: English
• Keywords: induced pluripotent stem cells; disease models, animal; amyloid beta-peptides; mice; Alzheimer disease; neural stem cells; animals; memory; FFR; animals, genetically modified; Caenorhabditis elegans; neurons; mitophagy; male; hippocampus; female