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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Mitochondria as a target for neuroprotection: role of methylene blue and photobiomodulation
TL;DR: This review will discuss two widely studied approaches for the improvement of brain mitochondrial respiration, methylene blue (MB) and photobiomodulation (PBM) with similar beneficial effects on mitochondrial function, oxidative damage, inflammation, and subsequent behavioral symptoms.
Journal ArticleDOI
Mitophagy regulates integrity of mitochondria at synapses and is critical for synaptic maintenance.
TL;DR: This study reveals Rheb and Snapin as key players regulating mitochondrial homeostasis at synapses and provides new insights into mitophagy regulation of synaptic mitochondrial integrity, establishing a foundation for mitigating AD‐associated mitochondria deficits and synaptic damage throughMitophagy enhancement.
Journal ArticleDOI
Re-emphasizing early Alzheimer's disease pathology starting in select entorhinal neurons, with a special focus on mitophagy.
Asgeir Kobro-Flatmoen,Maria Jose Lagartos-Donate,Yahyah Aman,Paul Edison,Menno P. Witter,Evandro Fei Fang +5 more
TL;DR: The entorhinal cortex (EC) is a pivotal component of this memory system since it serves as the interface between the neocortex and the hippocampus, and recent evidence leads to believe that this population is made up of highly energy-demanding reelin-positive (RE+) projection neurons as mentioned in this paper.
Journal ArticleDOI
Agephagy - Adapting Autophagy for Health During Aging
Eleanor R. Stead,Jorge Iván Castillo-Quan,Jorge Iván Castillo-Quan,Victoria E. Martinez Miguel,Celia Lujan,Robin Ketteler,Kerri J. Kinghorn,Ivana Bjedov +7 more
TL;DR: As an emerging and critical process in aging, this review will highlight how autophagy can be modulated for health improvement.
Journal ArticleDOI
Spatial Transcriptomics Reveals Genes Associated with Dysregulated Mitochondrial Functions and Stress Signaling in Alzheimer Disease.
José Fernández Navarro,Deborah L. Croteau,Aleksandra Jurek,Zaneta Andrusivova,Beimeng Yang,Yue Wang,Benjamin Ogedegbe,Tahira Riaz,Mari Støen,Claus Desler,Lene Juel Rasmussen,Tone Tønjum,Marie-Christine Galas,Joakim Lundeberg,Vilhelm A. Bohr,Vilhelm A. Bohr +15 more
TL;DR: A rich resource of spatially differentially expressed genes may contribute to understanding AD pathology and identify Bok, implicated in mitochondrial physiology and cell death, as a spatially downregulated gene in the hippocampus of mouse and human AD brains.
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