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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Mitochondrial dysfunction and Alzheimer’s disease: prospects for therapeutic intervention
TL;DR: The AD-related mitochondrial pathways and their small-molecule modulators that have therapeutic potential are surveyed and the current challenges and future perspectives of ongoing research are overviewed.
Journal ArticleDOI
The Protective Effects of Osteocyte‐Derived Extracellular Vesicles Against Alzheimer's Disease Diminished with Aging
Yaling Jiang,Zhenxing Wang,Xi-Xi Liu,Mei-dan Wan,Yi-Wei Liu,Bin Jiao,Xinxin Liao,Zhongyong Luo,Yi-Yi Wang,Chun-Gu Hong,Yi-Juan Tan,Ling Weng,Yafang Zhou,Shan-Shan Rao,Jia Cao,Zheng Zhao Liu,Teng-Fei Wan,Yuan-chao Zhu,Huiqing Xie,Lu Shen +19 more
TL;DR: The role of OCY‐EV is uncovered as a regulator of brain health, suggesting a novel mechanism in bone‐brain communication in Alzheimer's disease and osteoporosis, and its benefits are diminished in aged osteocyte‐derived EVs (OCYAged‐EVs).
Journal ArticleDOI
Pharmacological inhibition of USP30 activates tissue-specific mitophagy
TL;DR: In this paper, a USP30 inhibitor has been shown to increase mitophagy in vitro and in vivo in mice, without affecting the cardiac function of the mitochondria of the mt-Keima mice.
Journal ArticleDOI
Mitochondrial dysfunctions, oxidative stress and neuroinflammation as therapeutic targets for neurodegenerative diseases: An update on current advances and impediments
Muneeb U. Rehman,Nouroz Sehar,Nawab John Dar,Andleeb Khan,Azher Arafah,Summya Rashid,Shahzada Mudasir Rashid,Majid Ahmad Ganaie +7 more
TL;DR: A review of the major findings and advancements in recent years focusing on shared mechanisms for better understanding might become beneficial in searching more potent pharmacological interventions thereby reducing the onset or severity of various NDs as discussed by the authors .
Journal ArticleDOI
Mitophagy Regulates Neurodegenerative Diseases.
TL;DR: In this article, the authors introduce molecular mechanisms and signaling pathways behind mitophagy regulation and focus on the recent advances in understanding the potential role of mitophathy in the pathogenesis of major neurodegenerative diseases (Parkinson's, Alzheimer's, Huntington's, etc.) and aging.
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