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

被引：1514

作者：

Fang, Evandro F. ^{[1
,2
,3
,12
]}

Hou, Yujun ^{[1
]}

Palikaras, Konstantinos ^{[4
,5
]}

Adriaanse, Bryan A. ^{[6
]}

Kerr, Jesse S. ^{[1
]}

Yang, Beimeng ^{[1
]}

Lautrup, Sofie ^{[1
]}

Hasan-Olive, Md Mahdi ^{[2
,3
]}

Caponio, Domenica ^{[2
,3
]}

Dan, Xiuli ^{[1
]}

Rocktaschel, Paula ^{[6
]}

Croteau, Deborah L. ^{[1
]}

Akbari, Mansour ^{[7
]}

Greig, Nigel H. ^{[8
]}

Fladby, Tormod ^{[9
,10
]}

Nilsen, Hilde ^{[2
,3
]}

Cader, M. Zameel ^{[6
]}

Mattson, Mark P. ^{[11
,12
]}

Tavernarakis, Nektarios ^{[4
,5
]}

Bohr, Vilhelm A. ^{[1
,7
]}

机构：

[1] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA

[2] Univ Oslo, Dept Clin Mol Biol, Lorenskog, Norway

[3] Akershus Univ Hosp, Lorenskog, Norway

[4] Fdn Res & Technol Hellas, Inst Mol Biol & Biotechnol, Iraklion, Greece

[5] Univ Crete, Dept Basic Sci, Fac Med, Iraklion, Greece

[6] Univ Oxford, Weatherall Inst Mol Med, Oxford, England

[7] Univ Copenhagen, Ctr Hlth Aging, Copenhagen, Denmark

[8] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA

[9] Univ Oslo, Inst Clin Med, Div Med & Lab Sci, Fac Med, Oslo, Norway

[10] Akershus Univ Hosp, Dept Neurol, Lorenskog, Norway

[11] NIA, Lab Neurosci, NIH, Baltimore, MD 21224 USA

[12] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA

来源：

NATURE NEUROSCIENCE | 2019年 / 22卷 / 03期

基金：

欧洲研究理事会; 美国国家卫生研究院;

关键词：

A-BETA; LIFE-SPAN; NEURONS; MICROGLIA; AUTOPHAGY; PROTEIN; ELEGANS; PHOSPHORYLATION; FEATURES; BRAIN;

D O I：

10.1038/s41593-018-0332-9

中图分类号：

Q189 [神经科学];

学科分类号：

071006 [神经生物学];

摘要：

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-beta (A beta) 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 A beta(1-42) and A beta(1-40) and prevents cognitive impairment in an APP/PS1 mouse model through microglial phagocytosis of extracellular A beta 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.

引用

页码：401 / +

页数：15

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