Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by memory loss and multiple cognitive impairments. Several decades of intense research have revealed that multiple cellular changes are implicated in the development and progression of AD, including mitochondrial damage, synaptic dysfunction, amyloid beta (Aβ) formation and accumulation, hyperphosphorylated tau (P-Tau) formation and accumulation, deregulated microRNAs, synaptic damage, and neuronal loss in patients with AD. Among these, mitochondrial dysfunction and synaptic damage are early events in the disease process. Recent research also revealed that Aβ and P-Tau-induced defective autophagy and mitophagy are prominent events in AD pathogenesis. Age-dependent increased levels of Aβ and P-Tau reduced levels of several autophagy and mitophagy proteins. In addition, abnormal interactions between (1) Aβ and mitochondrial fission protein Drp1; (2) P-Tau and Drp1; and (3) Aβ and PINK1/parkin lead to an inability to clear damaged mitochondria and other cellular debris from neurons. These events occur selectively in affected AD neurons. The purpose of our article is to highlight recent developments of a Aβ and P-Tau-induced defective autophagy and mitophagy in AD. This article also summarizes several aspects of mitochondrial dysfunction, including abnormal mitochondrial dynamics (increased fission and reduced fusion), defective mitochondrial biogenesis, reduced ATP, increased free radicals and lipid peroxidation, and decreased cytochrome c oxidase (COX) activity and calcium dyshomeostasis in AD pathogenesis. Our article also discusses how reduced levels of Drp1, Aβ, and P-Tau can enhance the clearance of damaged mitochondria and other cellular debris by autophagy and mitophagy mechanisms.
Highlights
Internal Medicine Department, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, Garrison Institute on Aging, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, Garrison Institute on Aging, South West Campus, Texas Tech University Health Sciences Center, 6630 S
Aβ induces much of the mitochondrial dysfunction, including oxidative stress, which contributes to phosphorylation of tau, mtDNA damage, and further Aβ interaction with Drp1, Aβ-binding alcohol dehydrogenase (ABAD) and CypD, loss of cytochrome c oxidase (COX) activity, impaired gating of the mitochondrial permeability transition pore, loss of membrane potential, and loss of cardiolipins [2,14]
Dendritic spines were reduced in APP mice. These observations strongly suggest that the hippocampal accumulation of mutant APP and Aβ are responsible for mitochondrial dysfunction and synaptic damage and defective autophagy and mitophagy in APP mice [73]
Summary
Alzheimer’s disease (AD) is an end-of-life neurodegenerative disease characterized by the presence of amyloid beta (Aβ) peptides (which collect to form senile plaques), as well as the formation and accumulation of hyperphosphorylated tau and neurofibrillary tangles (NFTs) in the brains of AD patients [1,2,3,4,5,6,7]. Aβ induces much of the mitochondrial dysfunction, including oxidative stress, which contributes to phosphorylation of tau, mtDNA damage, and further Aβ interaction with Drp, Aβ-binding alcohol dehydrogenase (ABAD) and CypD, loss of cytochrome c oxidase (COX) activity, impaired gating of the mitochondrial permeability transition pore, loss of membrane potential, and loss of cardiolipins [2,14]. In severely chronic diseases such as AD, mitophagy is impaired [48] This is due to changes in the structural conformation of amyloid-beta protein to a disease-causing conformation, phosphorylated tau damage, and resultant cellular and mitochondrial damage [49,50]
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