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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Diabetes and Alzheimer’s Disease: Might Mitochondrial Dysfunction Help Deciphering the Common Path?
TL;DR: A growing number of clinical and epidemiological studies support the hypothesis of a tight correlation between type 2 diabetes mellitus (T2DM) and the development risk of Alzheimer's disease (AD) as mentioned in this paper.
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Teaching the basics of repurposing mitochondria-targeted drugs: From Parkinson's disease to cancer and back to Parkinson's disease.
TL;DR: It is proposed that mitochondrial targeting stimulates conservation of cellular energy critical for neuronal cell survival, whereas the energy conservation mechanism inhibits proliferation of cancer cells by depriving the energy necessary for cancer cell growth.
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Mitochondria and early-life adversity.
Emily Zitkovsky,Emily Zitkovsky,Teresa E. Daniels,Teresa E. Daniels,Audrey R. Tyrka,Audrey R. Tyrka +5 more
TL;DR: Early-life adversity (ELA), which includes maltreatment, neglect, or severe trauma in childhood, increases the life-long risk for negative health outcomes as mentioned in this paper, and mitochondria play a key role in the stress response and may be an important mechanism by which stress is transduced into biological risk for disease.
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Mitochondria targeting drugs for neurodegenerative diseases—Design, mechanism and application
TL;DR: In this paper , a review of mitochondria targeting drugs for the treatment of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease is presented, where the authors elaborately address the strategy to design mitochondria-targeting drugs, the rescue mechanism of respective mitochondrial targeting drugs, and how to evaluate the therapeutic effect.
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Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD+ signaling.
Mustafa Nazir Okur,Evandro Fei Fang,Evandro Fei Fang,Elayne M. Fivenson,Vinod Tiwari,Deborah L. Croteau,Vilhelm A. Bohr,Vilhelm A. Bohr +7 more
TL;DR: Support is provided for the interconnection between major causative aging theories, DNA damage accumulation, mitochondrial dysfunction, and compromised mitophagy/autophagy, which contribute to an accelerated aging program that can be averted by cellular NAD+ restoration.
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.