Role of mitochondrial homeostasis and dynamics in Alzheimer's disease

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that affects a staggering percentage of the aging population and causes memory loss and cognitive decline. Mitochondrial abnormalities can be observed systemically and in brains of patients suffering from AD, and may account for part of the disease phenotype. In this review, we summarize some of the key findings that indicate mitochondrial dysfunction is present in AD-affected subjects, including cytochrome oxidase deficiency, endophenotype data, and altered mitochondrial morphology. Special attention is given to recently described perturbations in mitochondrial autophagy, fission-fusion dynamics, and biogenesis. We also briefly discuss how mitochondrial dysfunction may influence amyloidosis in Alzheimer’s disease, why mitochondria are a valid therapeutic target, and strategies for addressing AD-specific mitochondrial dysfunction.

A Caenorhabditis elegans–based assay recognizes immunoglobulin light chains causing heart amyloidosis

“…21,39 The common pattern of damage exerted by cardiotoxic LCs and Ab oligomers on the worm's pharyngeal cells supports the hypothesis of shared pathways of toxicity between the 2 proteins. One of these, as described later, may involve mitochondria, which are known early targets of damage in Alzheimer disease 40,41 and are particularly abundant in both brain and cardiac muscular cells.…”

Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity

“…Clinical trials for AD focused primarily on counteracting Aβ aggregation in the brain, considered the key pathogenic mechanism 5 . However, AD is a complex multifactorial disease 6 and mitochondrial dysfunction emerged as a common pathological hallmark 7 . Mitochondrial abnormalities in AD include decreased mitochondrial respiration and activity and alterations in mitochondrial morphology 7 ; however, the relevance of other aspects of mitochondrial homeostasis, such as mitochondrial proteostasis, to the pathogenesis of AD is still largely unknown.…”

Hypoxia-Up-Regulated Mitochondrial Movement Regulator Does Not Contribute to the APP/PS1 Double Transgenic Mouse Model of Alzheimer's Disease

“…For more than two decades, the amyloid cascade hypothesis has occupied an important position in research on the pathogenesis of AD; however, the mitochondrial cascade hypothesis also gradually comes up [2]. Mitochondrial dysfunction in AD consists of mitochondrial respiratory chain dysfunction, impaired mitochondrial biogenesis, abnormal mitochondrial dynamics, impaired axonal transport of mitochondria and abnormal mitochondrial autophagy [3,4,5,6,7], which leads to increased reactive oxygen species, decreased adenosine triphosphate and further contributes to neuronal damage in AD. Mitochondria-mediated impairments of autophagy and the microtubule network contribute to amyloid-β deposition and tau hyperphosphorylation [8].…”