Mitophagy ameliorates Aβ and p-Tau pathologies, and cognitive deficits, in experimental models of Alzheimer’s disease

Accumulation of damaged mitochondria is a hallmark of human aging and age-related neurodegenerative pathologies, including Alzheimer’s disease (AD). However, the molecular mechanisms of the impaired mitochondrial homeostasis and their relationship to AD are still elusive. Here we provide evidence that mitophagy, a cellular process mediating selective clearance of dysfunctional mitochondria, is impaired in AD patient hippocampus, in iPSC-derived human neurons and in animal AD models. In C. elegans models of AD, pharmacological stimulation of mitophagy reverses memory impairment through a PINK-1, PDR-1 and DCT-1 dependent pathway. Mitophagy induction diminishes the levels of insoluble amyloid-β (Aβ)1-42 and Aβ1-40 peptide isoforms and prevents cognitive impairment in AD mice by a mechanism involving microglial phagocytosis of extracellular Aβ plaques and suppression of neuroinflammation. Furthermore, mitophagy abolishes AD-related Tau hyperphosphorylation in human neuronal cells and reverses memory impairment in transgenic Tau nematodes. Our findings suggest that impaired removal of defective mitochondria is a pivotal event in AD pathogenesis. Interventions that stimulate mitophagy therefore have therapeutic potential in the prevention and treatment of AD. APP/PS1 mice were treated with either vehicle (DMSO, N=7) or Urolithin A (UA, 200 mg/kg/day, N=6) by gavage from 6 months until 8 months of age, while wild-type (WT) littermates (N=6) were treated with vehicle in the same manner.