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
Circulating cell-free mitochondrial DNA in brain health and disease: A systematic review and meta-analysis.
Sarah Sohyun Park,Sarah Sohyun Park,Hyunjin Jeong,Hyunjin Jeong,Ana Cristina Andreazza,Ana Cristina Andreazza +5 more
TL;DR: In this article, the brain is one of the most energy-consuming organs in the human brain and mitochondria are released from the cell as a result of mitochondrial dysfunction or apoptosis.
Journal ArticleDOI
Methods to detect mitophagy in neurons during disease.
TL;DR: This review will introduceMitophagy pathways studied in neurons and evaluate current techniques available to investigate mitophagy and introduce PINK1/Parkin and Mul1, which function at the cellular level.
Journal ArticleDOI
The Role of Mitophagy in Various Neurological Diseases as a Therapeutic Approach
Simranjit Kaur,Neelam Sharma,Vishal Kumar,Deepali Sharma,B Parimaladevi Devi,Lakshay Kapil,Charan Singh,Arti Singh +7 more
Journal ArticleDOI
The Therapeutic Relevance of Urolithins, Intestinal Metabolites of Ellagitannin-Rich Food: A Systematic Review of In Vivo Studies
TL;DR: This systematic review methodically discusses the therapeutic prospects of urolithins and provides scientific justification for the potential development of Urolithin A as a potent natural mitophagy inducer for anti-ageing purposes.
Posted ContentDOI
ECSIT prevents Alzheimer’s disease pathology by regulating neuronal mitochondrial ROS and mitophagy
Alice Lepelley,Lauren S. Vaughn,Agnieszka Staniszewski,Hong Zhang,Fang Du,Peter Koppensteiner,Zeljko Tomljanovic,Flávia R.G. Carneiro,Flávia R.G. Carneiro,Andrew F. Teich,Ipe Ninan,Shirley ShiDu Yan,Thomas S. Postler,Matthew S. Hayden,Ottavio Arancio,Sankar Ghosh +15 more
TL;DR: It is demonstrated that levels of ECSIT, a mitochondrial oxidative phosphorylation (OxPhos) complex I (CI)-associated protein, are reduced in AD-affected brains and likely contribute to oxidative stress, neuroinflammation and AD pathogenesis.
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.