Defective mitophagy and synaptic degeneration in Alzheimer's disease: Focus on aging, mitochondria and synapse

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory loss and multiple cognitive impairments. AD is marked by multiple cellular changes, including deregulation of microRNAs, activation of glia and astrocytes, hormonal imbalance, defective mitophagy, synaptic degeneration, in addition to extracellular neuritic amyloid-beta (Aβ) plaques, phosphorylated tau (P-tau), and intracellular neurofibrillary tangles (NFTs). Recent research in AD revealed that defective synaptic mitophagy leads to synaptic degeneration and cognitive dysfunction in AD neurons. Our critical analyses of mitochondria and Aβ and P-tau revealed that increased levels of Aβ and P-Tau, and abnormal interactions between Aβ and Drp1, P-Tau and Drp1 induced increased mitochondrial fragmentation and proliferation of dysfunctional mitochondria in AD neurons and depleted Parkin and PINK1 levels. These events ultimately lead to impaired clearance of dead and/or dying mitochondria in AD neurons. The purpose of our article is to highlight the recent research on mitochondria and synapses in relation to Aβ and P-tau, focusing on recent developments.

Keywords: Alzheimer's disease; Amyloid beta; Amyloid precursor protein; Autophagy; Mitophagy; Oxidative phosphorylation; Phosphorylated tau.