| Literature DB >> 30742114 |
Evandro F Fang1,2, Yujun Hou3, Konstantinos Palikaras4,5, Bryan A Adriaanse6, Jesse S Kerr3, Beimeng Yang3, Sofie Lautrup3, Md Mahdi Hasan-Olive7, Domenica Caponio7, Xiuli Dan3, Paula Rocktäschel6, Deborah L Croteau3, Mansour Akbari8, Nigel H Greig9, Tormod Fladby10,11, Hilde Nilsen7, M Zameel Cader6, Mark P Mattson12,13, Nektarios Tavernarakis4,5, Vilhelm A Bohr14,15.
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.Entities:
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Year: 2019 PMID： 30742114 PMCID： PMC6693625 DOI： 10.1038/s41593-018-0332-9
Source DB: PubMed Journal: Nat Neurosci ISSN： 1097-6256 Impact factor: 24.884