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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Ageing as a risk factor for neurodegenerative disease.
Yujun Hou,Xiuli Dan,Mansi Babbar,Yong Wei,Steen G. Hasselbalch,Deborah L. Croteau,Vilhelm A. Bohr,Vilhelm A. Bohr +7 more
TL;DR: Hallmarks of ageing — genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, cellular senescence, stem cell exhaustion and altered intercellular communication — correlate with susceptibility to neurodegenerative disease.
Journal ArticleDOI
Reactive Oxygen Species-Induced Lipid Peroxidation in Apoptosis, Autophagy, and Ferroptosis.
Lianjiu Su,Jiahao Zhang,Hernando Gomez,Raghavan Murugan,Xing Hong,Dongxue Xu,Fan Jiang,Zhiyong Peng,Zhiyong Peng +8 more
TL;DR: This review discussed how ROS propagate lipid peroxidation chain reactions and how the products of lipidperoxidation initiate apoptosis and autophagy in current models, and summarized lipid per oxidation in pathological conditions of critical illness.
Journal ArticleDOI
Synergy between amyloid-β and tau in Alzheimer’s disease
TL;DR: Emerging evidence for an interaction between Aβ and tau during Alzheimer’s disease (AD) progression that challenges the classical linear trajectory model and offers a new perspective on AD pathophysiology and therapy is reviewed.
Journal ArticleDOI
Mitochondria dysfunction in the pathogenesis of Alzheimer's disease: recent advances.
TL;DR: This review will discuss mechanisms underlying mitochondrial dysfunction with a focus on the loss of mitochondrial structural and functional integrity in AD including mitochondrial biogenesis and dynamics, axonal transport, ER-mitochondria interaction, mitophagy and mitochondrial proteostasis.
Journal ArticleDOI
NAD+ metabolism and its roles in cellular processes during ageing
Anthony J. Covarrubias,Anthony J. Covarrubias,Rosalba Perrone,Alessia Grozio,Eric Verdin,Eric Verdin +5 more
TL;DR: Nicotinamide adenine dinucleotide (NAD+) is a coenzyme for redox reactions, making it central to energy metabolism and is also an essential cofactor for non-redox NAD+-dependent enzymes, including sirtuins, CD38 and poly(ADP-ribose) polymerases as discussed by the authors.
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