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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NAD + supplementation prevents STING-induced senescence in ataxia telangiectasia by improving mitophagy
Beimeng Yang,Xiuli Dan,Yujun Hou,Jong Hyuk Lee,Noah Wechter,Sudarshan Krishnamurthy,Risako Kimura,Mansi Babbar,Tyler G Demarest,Ross A. McDevitt,Shiliang Zhang,Yongqing Zhang,Mark P. Mattson,Deborah L. Croteau,Vilhelm A. Bohr,Vilhelm A. Bohr +15 more
TL;DR: In this paper, the authors demonstrate that boosting intracellular NAD+ levels with nicotinamide riboside (NR) prevents senescence and SASP by promoting mitophagy in a PINK1-dependent manner.
Journal ArticleDOI
The NAD+-mitophagy axis in healthy longevity and in artificial intelligence-based clinical applications
Yahyah Aman,Johannes Frank,Sofie Lautrup,Adrian Matysek,Zhangming Niu,Guang Yang,Liu Shi,Linda H. Bergersen,Jon Storm-Mathisen,Lene Mydland Rasmussen,Vilhelm A. Bohr,Hilde Nilsen,Evandro Fei Fang +12 more
TL;DR: Advances in the understanding of the molecular and cellular roles of NAD+ in mitophagy will lead to novel approaches for facilitating healthy mitochondrial homoeostasis that may serve as a promising therapeutic strategy to counter ageing-associated pathologies and/or accelerated ageing.
Journal ArticleDOI
The role of mitochondrial dysfunction in Alzheimer's disease pathogenesis
TL;DR: The Amyloid Cascade Model does not readily account for various parameters associated with Alzheimer's disease (AD), and a unified model correctly identifying the pathogenesis of AD is greatly needed to inform the development of successful therapeutics.
Journal ArticleDOI
Spotlight on Ferroptosis: Iron-Dependent Cell Death in Alzheimer's Disease.
Azhaar Ashraf,Po-Wah So +1 more
TL;DR: Clinical trials that provide the rationale for targeting ferroptosis to delay the pathogenesis of Alzheimer’s disease (AD) are reviewed, potentially of relevance to other neurodegenerative diseases.
Journal ArticleDOI
Mitophagy and DNA damage signaling in human aging.
TL;DR: The molecular signaling pathways involved in regulation of DNA damage and repair and of mitophagy are discussed, and the opportunities for clinical interventions targeting these processes to improve the quality of life during aging are highlighted.
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