Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer's disease.
Evandro Fei FangYujun HouKonstantinos PalikarasBryan A AdriaanseJesse S KerrBeimeng YangSofie LautrupMd Mahdi Hasan-OliveDomenica CaponioXiuli DanPaula RocktäschelDeborah L CroteauMansour AkbariNigel H GreigTormod FladbyHilde NilsenM Zameel CaderMark P MattsonNektarios TavernarakisVilhelm A BohrPublished in: Nature neuroscience (2019)
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.
Keyphrases
- cognitive impairment
- endothelial cells
- mouse model
- nlrp inflammasome
- end stage renal disease
- high glucose
- cell death
- cerebrospinal fluid
- chronic kidney disease
- diabetic rats
- cognitive decline
- traumatic brain injury
- transcription factor
- working memory
- type diabetes
- spinal cord
- oxidative stress
- induced pluripotent stem cells
- newly diagnosed
- pi k akt
- ejection fraction
- adipose tissue
- cell proliferation
- cell cycle arrest
- cerebral ischemia
- patient reported outcomes
- spinal cord injury
- drug induced
- neuropathic pain
- tyrosine kinase
- pluripotent stem cells
- endoplasmic reticulum
- patient reported
- single molecule
- high speed
- wild type