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
Posted ContentDOI
A method to identify physical, chemical and biological factors that trigger 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,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 +23 more
TL;DR: It is shown that DNA-damaging agent 4-nitroquinoline-1-oxide (4NQO) killed human non-malignant as well as malignant cells and the small roundworm C. elegans when combined with A-1155463, but not with Bcl-2- or Mcl- 1-specific agents.
Journal ArticleDOI
The Tricky Connection between Extracellular Vesicles and Mitochondria in Inflammatory-Related Diseases
Tommaso Di Mambro,Giulia Pellielo,Esther Densu Agyapong,Maria Tereza Carinci,Diego Chianese,Carlotta Giorgi,Giampaolo Morciano,Simone Patergnani,Paolo Pinton,Alessandro Rimessi +9 more
TL;DR: The relationship between EVs and mitochondria in inflammation is an active area of research, although further studies are needed to fully understand the mechanisms involved and how they may be targeted for therapeutic purposes as discussed by the authors .
Journal ArticleDOI
The role of nutrition and the Mediterranean diet on the trajectories of cognitive decline
TL;DR: In this article , the authors reviewed the methodological challenges of comparing studies of dietary interventions and concluded that acting on modifiable risk factors, especially in midlife, is a good strategy for reducing the burden of dementia.
Posted ContentDOI
Manipulation of neuronal activity in the entorhinal-hippocampal circuit affects intraneuronal amyloid-β levels
Christiana Bjorkli,Nora C Ebbesen,Joshua B. Julian,Menno P. Witter,Axel Sandvig,Ioanna Sandvig +5 more
TL;DR: Early intraneuronal Aβ levels in the downstream HPC correlated with activity levels in superficial layers of LEC, with the subiculum being the earliest subregion involved, and these findings give evidence to early AD neuropathology originating in select neuronal populations.
Journal ArticleDOI
Alzheimer's Amyloid-β Accelerates Cell Senescence and Suppresses the SIRT1/NRF2 Pathway in Human Microglial Cells
TL;DR: It is revealed that Aβ accelerates human microglial senescence mainly through its suppression of the SIRT1/NRF2 pathway and suggested that genetic and pharmaceutical rescue of Sirtuin-1 may provide a potential alternative treatment.
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.