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
More filters
Journal ArticleDOI
Chemical, Physical and Biological Triggers of Evolutionary Conserved Bcl-xL-Mediated Apoptosis.
Aleksandr Ianevski,Evgeny Kulesskiy,Klara Krpina,Guofeng Lou,Yahyah Aman,Andrii Bugai,Koit Aasumets,Yevhen Akimov,Daria Bulanova,Kiira Gildemann,Albert F. Arutyunyan,Olga Yu. Susova,Alexei L. Zhuze,Ping Ji,Wei Wang,Toril Holien,Marit Bugge,Eva Zusinaite,Valentyn Oksenych,Hilde Lysvand,Joachim M. Gerhold,Magnar Bjørås,Pål Johansen,Anders Waage,Caroline A. Heckman,Evandro Fei Fang,Denis E. Kainov,Denis E. Kainov,Denis E. Kainov +28 more
TL;DR: Several biological, chemical and physical triggers of the evolutionarily conserved Bcl-xL-mediated apoptotic pathway are identified, shedding light on strategies and targets for novel drug development.
Journal ArticleDOI
Some Candidate Drugs for Pharmacotherapy of Alzheimer's Disease.
TL;DR: In this article, the PUBMED, Medical Subject Heading and Clinical Trials databases were used for searching relevant data for Alzheimer's disease (AD; progressive neurodegenerative disorder) associated with cognitive and functional impairment with accompanying neuropsychiatric symptoms.
Journal ArticleDOI
Mitochondrial Calcium Signaling as a Therapeutic Target for Alzheimer's Disease.
TL;DR: In this article, the authors discuss the molecular players involved in mitochondrial Ca2+ dysregulation and the pharmacotherapies that target this dysregulation, and discuss how to reestablish mitochondrial ca2+ homeostasis may aid the development of novel AD therapeutic interventions.
Journal ArticleDOI
A Glimmer of Hope: Maintain Mitochondrial Homeostasis to Mitigate Alzheimer's Disease.
TL;DR: This review aims to illustrate mitochondrial biology with a focus on mitophagy and propose strategies to treat AD while maintaining mitochondrial homeostasis and pointing out the possibility of a novel therapy.
Journal ArticleDOI
Mitophagy impairment in neurodegenerative diseases: Pathogenesis and therapeutic interventions.
TL;DR: A review of mitophagy in neurodegenerative diseases can be found in this article, which summarizes the abnormalities in different Mitophagy pathways and their association with different NDDs.
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.