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
New Insights into Molecular Mechanisms Underlying Neurodegenerative Disorders.
Jiale Liu,Wenjie Duan,Yushu Deng,Qiankun Zhang,Rong Li,J. Long,Waqas Ahmed,Chenyang Gu,Hengsen Cai,Yong Hu,Lukui Chen +10 more
TL;DR: A review of the existing literature and insights into the molecular mechanisms underlying neurodegenerative diseases is presented in this paper , where the authors also provide new insights into new molecular theories and mechanisms.
Journal ArticleDOI
Pathogenesis, Animal Models, and Drug Discovery of Alzheimer's Disease.
TL;DR: In this article , the authors provide more novel ideas on the complex pathophysiological mechanisms of Alzheimer's disease, including classical pathogenesis and a variety of possible pathogenesis that have been proposed in recent years.
Journal ArticleDOI
Galangin Rescues Alzheimer’s Amyloid-β Induced Mitophagy and Brain Organoid Growth Impairment
TL;DR: In this article , a 3D human brain organoid culturing system was used to study the role of mitophagy in AD and to assess potential mitophag-targeting therapies.
Journal ArticleDOI
Caenorhabditis elegans as a Model System to Study Human Neurodegenerative Disorders
TL;DR: In this article , a review of C. elegans used to study neurodegeneration and highlighting their contribution in the effort to dissect the molecular basis of human diseases and identify novel gene targets with therapeutic potential is presented.
Journal ArticleDOI
Urolithin A exhibits a neuroprotective effect against Alzheimer’s disease by inhibiting DYRK1A activity
TL;DR: Zhang et al. as discussed by the authors performed kinase profiling to show that dual-specific tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is the main target of Urolithin A (UA).
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.