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
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Sustained intracellular calcium rise mediates neuronal mitophagy in models of autosomal dominant optic atrophy
Marta Zaninello,Marta Zaninello,Konstantinos Palikaras,Aggeliki Sotiriou,Nektarios Tavernarakis,Nektarios Tavernarakis,Luca Scorrano +6 more
TL;DR: In this paper, the authors showed that mitophagy in ADOA depends on Ca2+-calcineurin-AMPK signaling cascade and showed that sustained Ca 2+ levels activate calcineurins and AMPK, placed in the same genetic pathway regulating axonal mitochondrial density.
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Caenorhabditis elegans as a possible model to screen anti-Alzheimer's therapeutics.
TL;DR: This review supports the versatile nature of C. elegans and collates that it is a well-suited model to elucidate various molecular mechanisms by which AD therapeutics elicit their pharmacological effects and has the potential for further scientific exploration.
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RP1, a RAGE antagonist peptide, can improve memory impairment and reduce Aβ plaque load in the APP/PS1 mouse model of Alzheimer's disease.
Yi-yun Huang,Nian Fang,Hui-ru Luo,Feng Gao,Yao Zou,Li-li Zhou,Qing-ping Zeng,Shi-song Fang,Fei Xiao,Qing Zheng +9 more
TL;DR: RP1 significantly improves the AD symptoms of APP/PS1 mice, and the RNA-seq results provide new ideas for elucidating the possible mechanisms of RP1 treatment.
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Amyotrophic lateral sclerosis alters the metabolic aging profile in patient derived fibroblasts.
Margarita Gerou,Benjamin A. Hall,Ryan Woof,Jessica Allsop,Stephen J. Kolb,Kathrin Meyer,Pamela J. Shaw,Scott P. Allen +7 more
TL;DR: In this article, the effect of aging on the metabolic profile of fibroblasts derived from ALS cases compared to controls was examined using a newly established phenotypic metabolic approach, and the results suggest that supplementing those pathways may protect against age related metabolic dysfunction in ALS.
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Mitochondrial Quality Control Strategies: Potential Therapeutic Targets for Neurodegenerative Diseases?
Di Hu,Zunren Liu,Xin Qi +2 more
TL;DR: In this article, the authors summarize recent progress that underscores the essential role of impaired mitochondrial quality control pathways in the pathogenesis of neurodegenerative diseases and discuss the translational approaches targeting mitochondrial function with a focus on the restoration of mitochondrial integrity.
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