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
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Regulation of beta‐amyloid for the treatment of Alzheimer's disease: Research progress of therapeutic strategies and bioactive compounds
TL;DR: In this article , the authors discuss the importance of Aβ in the pathogenesis of Alzheimer's disease and summarize the latest progress in Aβ-related targets and compounds, and put forward the challenges and opportunities in the development of effective AD therapies.
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PARK15/FBXO7 is dispensable for PINK1/Parkin mitophagy in iNeurons and HeLa cell systems
Felix Kraus,Ellen A. Goodall,Ian R. Smith,Yizhi Jiang,Julia C. Paoli,Frank Adolf,Jiuchun Zhang,Joao A. Paulo,Brenda A. Schulman,J. Wade Harper +9 more
TL;DR: In this paper , the involvement of FBXO7 in depolarization and mtUPR-dependent mitophagy in the well-established HeLa and induced-neurons cell systems was examined.
Journal ArticleDOI
Building in vitro models of the brain to understand the role of APOE in Alzheimer’s disease
Rebecca L. Pinals,Li-Huei Tsai +1 more
TL;DR: Human induced pluripotent stem cell–based models of the brain will be key to unraveling the role of APOE ɛ4 in the interconnected cellular changes underlying Alzheimer’s disease.
Journal ArticleDOI
A Perspective on Autophagy and Transcription Factor EB in Alcohol-Associated Alzheimer's Disease.
Chen Zhang,Hao Chen,Yssa Ann Rodriguez,Xiaowen Ma,Russell H. Swerdlow,Jianhua Zhang,Wen-Xing Ding +6 more
TL;DR: In this paper , the authors discuss mechanisms of selective autophagy for mitochondria and protein aggregates and how these mechanisms are impaired by aging and alcohol consumption, and discuss potential genetic and pharmacological approaches for targeting autophag/mitophagy, as well as lysosomal and mitochondrial biogenesis, for the potential prevention and treatment of AD.
Journal ArticleDOI
Parkinson’s Disease: Are PINK1 Activators Inching Closer to the Clinic?
TL;DR: The activation of PINK1 by small molecules has emerged as a promising strategy in treating Parkinson's disease as mentioned in this paper , and recent progress in this area has raised excitement around pINK1 activators as PD treatments, and herein we offer insight into these developments and their potential to deliver much needed novel PD treatments.
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