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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Endosomal-lysosomal dysfunctions in Alzheimer's disease: Pathogenesis and therapeutic interventions.
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Chiral Nanoparticles Force Neural Stem Cell Differentiation to Alleviate Alzheimer's Disease
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Managing risky assets - mitophagy in vivo.
TL;DR: In this article, the authors explored the in vivo roles of mitophagy in mammalian systems, focusing on the best studied examples - mitophathy in neurodegeneration, cardiomyopathy, metabolism, and red blood cell development - to draw out common themes.
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Effects of Mild Excitotoxic Stimulus on Mitochondria Ca2+ Handling in Hippocampal Cultures of a Mouse Model of Alzheimer's Disease.
TL;DR: In this paper, the role of mitochondria and Ca2+ signaling in a model of Familial Alzheimer's disease and found early alterations in mitochondria physiology under stressful condition, namely, reduced maximal respiration, decreased ability to sustain membrane potential, and a slower return to basal matrix Ca 2+ levels after a mild excitotoxic stimulus.
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Crosstalk between Different DNA Repair Pathways Contributes to Neurodegenerative Diseases
Swapnil Gupta,Panpan You,Panpan You,Tanima SenGupta,Tanima SenGupta,Hilde Nilsen,Hilde Nilsen,Kulbhushan Sharma,Kulbhushan Sharma +8 more
TL;DR: In this article, the authors compare the strengths and limitations of established model systems to model human NDDs, ranging from C. elegans and mouse models towards advanced stem cell-based 3D models.
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