Molecular linkages among Aβ, tau, impaired mitophagy, and mitochondrial dysfunction in Alzheimer’s disease

While extracellular Aβ plaques and intracellular tau tangles are the classical disease-defining pathological features of Alzheimer’s disease (AD), defective mitophagy, and consequently, the accumulation of damaged mitochondria increase risk of AD and exacerbate AD progression. Mitophagy is a cellular autophagic process that selectively recognizes and degrades damaged or extraneous mitochondria. Defective autophagy and accumulation of damaged mitochondria are hallmarks of brain aging and causes/risks of age-related neurodegeneration. Here, we summarize recent progress on the molecular mechanisms connecting Aβ, tau, mitochondria, and mitophagy, and their links to AD. Mitophagic enhancement impedes memory loss in multiple animal models of AD, possibly through clearance of proteinopathies, elimination of inflammation, and enhancement of neuronal survival. Collectively, impaired removal of defective mitochondria is a pivotal event in AD pathogenesis and turning up mitophagy is a novel therapeutic strategy for the treatment of AD.