RRC ID 59342
著者 Fang EF, Hou Y, Palikaras K, Adriaanse BA, Kerr JS, Yang B, Lautrup S, Hasan-Olive MM, Caponio D, Dan X, Rocktäschel P, Croteau DL, Akbari M, Greig NH, Fladby T, Nilsen H, Cader MZ, Mattson MP, Tavernarakis N, Bohr VA.
タイトル Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer's disease.
ジャーナル Nat Neurosci
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 Aβ1-42 and Aβ1-40 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.
巻・号 22(3)
ページ 401-412
公開日 2019-3-1
DOI 10.1038/s41593-018-0332-9
PII 10.1038/s41593-018-0332-9
PMID 30742114
PMC PMC6693625
MeSH Alzheimer Disease / metabolism* Alzheimer Disease / pathology Alzheimer Disease / psychology Amyloid beta-Peptides / metabolism* Animals Animals, Genetically Modified Caenorhabditis elegans Disease Models, Animal Female Hippocampus / metabolism* Hippocampus / pathology* Induced Pluripotent Stem Cells Male Memory Mice Mitophagy* Neural Stem Cells Neurons / metabolism* Neurons / pathology*
IF 21.126
引用数 141
リソース情報
線虫 tm1779 tm376