Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease
Evandro Fei Fang,Yujun Hou,Konstantinos Palikaras,Bryan A. Adriaanse,Jesse S. Kerr,Beimeng Yang,Sofie Lautrup,Mahdi Hasan-Olive,Domenica Caponio,Xiuli Dan,P Rocktäschel,Deborah L. Croteau,Mansour Akbari,Nigel H. Greig,Tormod Fladby,Hilde Nilsen,M Z Cader,Mark P. Mattson,Nektarios Tavernarakis,Nektarios Tavernarakis,Vilhelm A. Bohr,Vilhelm A. Bohr +21 more
TLDR
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 is provided, suggesting that impaired removal of defective mitochondria is a pivotal event in AD pathogenesis and thatMitophagy represents a potential therapeutic intervention.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.read more
Citations
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Age-Associated Mitochondrial Dysfunction Accelerates Atherogenesis
Daniel J. Tyrrell,Muriel G. Blin,Jianrui Song,Sherri C. Wood,Min Zhang,Daniel A. Beard,Daniel R. Goldstein +6 more
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Mitochondria in the signaling pathways that control longevity and health span.
TL;DR: Evidence is reviewed that through reciprocal and multilevel functional interactions, mitochondria are implicated in the lifespan modulation function of these pathways, which altogether constitute a highly dynamic and complex system that controls the aging process.
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Mitophagy pathways in health and disease.
TL;DR: Killackey et al. review recent advances and major questions in the field of mitophagy, as well as implications forMitophagy in disease, and suggest several avenues for further research.
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Mitochondria and Calcium in Alzheimer's Disease: From Cell Signaling to Neuronal Cell Death.
TL;DR: Whether mitochondrial calcium transporters should be proposed as therapeutic candidates for the development of neuroprotective drugs against AD is discussed, and special emphasis on mitochondrial calcium is focused on.
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Mitophagy and NAD+ inhibit Alzheimer disease.
TL;DR: This cross-species study provides strong support for the ‘defective mitophagy hypothesis of AD etiology’, which is essential for clearance of damaged mitochondria to maintain mitochondrial homeostasis, ATP production, and neuronal activity and survival.
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