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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Cellular senescence at the crossroads of inflammation and Alzheimer's disease
Ana Guerrero,Ana Guerrero,Bart De Strooper,I. Lorena Arancibia-Carcamo,I. Lorena Arancibia-Carcamo +4 more
TL;DR: In this article, the role of cellular senescence as a driver of the aging phenotype was highlighted, and the current evidence that connects senescent cells with AD and neurodegeneration was discussed.
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Targeting mitophagy in Parkinson's disease
TL;DR: The genetic evidence supporting the role for mitophagy failure as a pathogenic mechanism in Parkinson’s disease is provided and the tractability of Mitophagy pathways and prospects for drug discovery are assessed and intervention points forMitophagy enhancement are considered.
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Control of Inflammation by Calorie Restriction Mimetics: On the Crossroad of Autophagy and Mitochondria.
Enrique Gabandé-Rodríguez,Enrique Gabandé-Rodríguez,Manuel M. Gómez de las Heras,Manuel M. Gómez de las Heras,María Mittelbrunn,María Mittelbrunn +5 more
TL;DR: The effects of some compounds classically known as modulators of autophagy and mitochondrial function, such as NAD+ precursors, metformin, spermidine, rapamycin, and resveratrol, on the control of the inflammatory cascade are outlined and how they could be involved in their ability to increase resilience to age-associated diseases.
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Loss of function of the mitochondrial peptidase PITRM1 induces proteotoxic stress and Alzheimer's disease-like pathology in human cerebral organoids.
María José Pérez,María José Pérez,Dina Ivanyuk,Dina Ivanyuk,Vasiliki Panagiotakopoulou,Vasiliki Panagiotakopoulou,Gabriele Di Napoli,Gabriele Di Napoli,Stefanie Kalb,Stefanie Kalb,Dario Brunetti,Rawaa Al-Shaana,Rawaa Al-Shaana,Stephan A. Kaeser,Stephan A. Kaeser,Sabine Anne-Kristin Fraschka,Mathias Jucker,Mathias Jucker,Massimo Zeviani,Carlo Viscomi,Michela Deleidi,Michela Deleidi +21 more
TL;DR: A novel concept of PITRM1-linked neurological syndrome is proposed whereby defects of mitochondrial presequence processing induce an early activation of UPR mt that, in turn, modulates cytosolic quality control pathways, which supports a mechanistic link between mitochondrial function and common neurodegenerative proteinopathies.
Journal ArticleDOI
Urolithin A-induced mitophagy suppresses apoptosis and attenuates intervertebral disc degeneration via the AMPK signaling pathway.
Jialiang Lin,Jinru Zhuge,Xuan-Qi Zheng,Yuhao Wu,Zengjie Zhang,Tianzhen Xu,Zaher Meftah,Hong-Ming Xu,Yaosen Wu,Naifeng Tian,Weiyang Gao,Yifei Zhou,Xiaolei Zhang,Xiang-Yang Wang +13 more
TL;DR: Investigation of the protective effect of UA-induced mitophagy on tert-butyl hydroperoxide-induced apoptosis in nucleus pulposus (NP) cells in vitro and in vivo suggested that UA could be a novel and effective therapeutic strategy for IDD.
References
More filters
Journal ArticleDOI
The genetics of caenorhabditis elegans
TL;DR: In this paper, the authors describe methods for the isolation, complementation and mapping of mutants of Caenorhabditis elegans, a small free-living nematode worm.
Journal ArticleDOI
A Simple Statistical Parameter for Use in Evaluation and Validation of High Throughput Screening Assays.
TL;DR: A screening window coefficient, called "Z- factor," is defined, which is reflective of both the assay signal dynamic range and the data variation associated with the signal measurements, and therefore is suitable for assay quality assessment.
Journal Article
The genetics of Caenorhabditis elegans.
TL;DR: Estimates of the induced mutation frequency of both the visible mutants and X chromosome lethals suggests that, just as in Drosophila, the genetic units in C. elegans are large.
Journal ArticleDOI
Alzheimer's Disease Is a Synaptic Failure
TL;DR: Mounting evidence suggests that this syndrome begins with subtle alterations of hippocampal synaptic efficacy prior to frank neuronal degeneration, and that the synaptic dysfunction is caused by diffusible oligomeric assemblies of the amyloid β protein.
Journal ArticleDOI
Triple-Transgenic Model of Alzheimer's Disease with Plaques and Tangles: Intracellular Aβ and Synaptic Dysfunction
Salvatore Oddo,Antonella Caccamo,Jason D. Shepherd,M. Paul Murphy,Todd E. Golde,Rakez Kayed,Raju Metherate,Mark P. Mattson,Yama Akbari,Frank M. LaFerla +9 more
TL;DR: The recapitulation of salient features of AD in these mice clarifies the relationships between Abeta, synaptic dysfunction, and tangles and provides a valuable model for evaluating potential AD therapeutics as the impact on both lesions can be assessed.