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Aging-Dependent Mitophagy Dysfunction in Alzheimer’s Disease

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Abstract

Alzheimer’s disease (AD) is the most common late-onset dementia characterized by the deposition of extracellular amyloid plaques and formation of intracellular neurofibrillary tangles, which eventually lead to neuronal loss and cognitive deficits. Multiple lines of evidence indicate that mitochondrial dysfunction is involved in the initiation and progression of AD. As essential machinery for mitochondrial quality control, mitophagy plays a housekeeping role in neuronal cells by eliminating dysfunctional or excessive mitochondria. At present, mounting evidence support that the activity of mitophagy markedly declines in human brains during aging. Impaired mitophagy and mitochondrial dysfunction were causally linked to bioenergetic deficiency, oxidative stress, microglial activation, and chronic inflammation, thereby aggravating the Aβ and tau pathologies and leading to neuron loss in AD. This review summarizes recent evidence for age-associated mitophagy decline during human aging and provides an overview of mitochondrial dysfunction involved in the process of AD. It also discusses the underlying mechanisms through which defective mitophagy leads to neuronal cell death in AD. Therapeutic interventions aiming to restore mitophagy functions can be used as a strategy for ameliorating AD pathogenesis.

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Abbreviations

Aβ:

Amyloid beta

AD:

Alzheimer disease

APP:

Amyloid precursor protein

IL-1β:

Interleukin-1β

ROS:

Reactive oxygen species

NFT:

Neurofibrillary tangles

TNF:

Tumor necrosis factor

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Funding

This work was supported by the National Natural Science Foundation of China (No. 81673209).

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  1. Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 Wenhuaxi Road, Jinan, 250012, Shandong, People’s Republic of China

    Mingxue Song, Xiulan Zhao & Fuyong Song

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Mingxue Song is the first author of this work, Xiulan Zhao is the co-author, and Fuyong Song is the corresponding author. All authors have read and approved the final manuscript.

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Song, M., Zhao, X. & Song, F. Aging-Dependent Mitophagy Dysfunction in Alzheimer’s Disease. Mol Neurobiol 58, 2362–2378 (2021). https://doi.org/10.1007/s12035-020-02248-y

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