Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease

By Evandro Fei Fang, Yujun Hou, K. Palikaras, Bryan A. Adriaanse, J. Kerr, Beimeng Yang, Sofie Lautrup, M. Hasan-Olive, D. Caponio, Xiuli Dan and 10 more. Nature Neuroscience, 2019

1,497 citations recorded by the source corpus.

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. The authors report that mitophagy is impaired in Alzheimer’s disease. Stimulation of mitophagy reverses cognitive deficits in nematode and mouse models of Alzheimer’s disease, suggesting a potential therapeutic intervention.

Subfields: Epidemiology, Neurology, Physiology

View Paper: https://www.semanticscholar.org/paper/69ce7d3fc73d68eca86a6e67a6158687aed1c8b1

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In Epidemiology

1. Koji Yamano
2. N. Matsuda
3. Miyuki Sato
4. Mashun Onishi
5. Koji Okamoto

In Neurology

1. Koji Yamano
2. N. Matsuda
3. Miyuki Sato
4. Mashun Onishi
5. Koji Okamoto

In Physiology

1. Koji Yamano
2. N. Matsuda
3. Miyuki Sato
4. Mashun Onishi
5. Koji Okamoto
6. Huaxi Xu

Citations in the corpus

• NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential (2020, background): “elegans to mice.(187,500,505,506) The increased activity and expression of CD38 following aging is responsible for the age-associated decrease in NAD level and defective mitochondrial function, which is at least partially regulated by the NAD/SIRT3 signaling pathway.”
• Cellular mitophagy: Mechanism, roles in diseases and small molecule pharmacological regulation (2023, background): “mechanisms that dependent on PINK1, Parkinson's disease-related-1 (PDR-1) or DAF-16/FOXO-controlled germline-tumor affecting-1 (DCT-1) [50].”
• The mitophagy pathway and its implications in human diseases (2023, background): “Restoration of mitophagy favors inhibition and reduction of Aβ plaques, elimination of tau hyperphosphorylation, and prevention of cognitive dysfunction.(177,202) Abnormal accumulation of tau protein also affects the function of mitophagy.”
• Molecular mechanisms and physiological functions of mitophagy (2021, positive): “Pharmacological or genetic stimulation of mito-phagy mitigates b -amyloid plaque formation and tau hyperphosphorylation, and reverses memory impairment (Sorrentino et al , 2017; Fang et al , 2019).”
• Aging and aging-related diseases: from molecular mechanisms to interventions and treatments (2022, background): “Mitochondrial dysfunction promotes tau phosphorylation through the activation of AMPK and excessive mitochondrial fission, which in turn impairs ATP production.(213) In addition, the PTEN-induced putative protein kinase 1 (PINK1)-Parkin pathway is important in mitophagy and in neuronal mitochondrial”
• Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020, background): “A recent study reports that impairment of mitophagic activity can induce synaptic dysfunction and trigger cognitive deficits by enhancing Aβ and tau accumulation, and stimulation of mitophagy reverses memory loss in nematode and mouse models of AD [519].”