Alzheimer’s disease (AD) is a progressive brain disorder characterized by memory loss and the accumulation of two insoluble protein aggregates, tau neurofibrillary tangles and beta-amyloid plaques. Widespread mitochondrial dysfunction also occurs and mitochondria from AD patients display changes in number, ultrastructure, and enzyme activities. Mitochondrial dysfunction in AD presumably links in some way to its other disease characteristics, either as a cause or consequence. This review characterizes AD-associated mitochondrial perturbations and considers their position in its pathologic hierarchy. It focuses on the crosstalk that occurs between mitochondria, nuclear gene expression, and cytosolic signaling pathways that serves to maintain cell homeostasis. To this point, recent evidence indicates mitochondria trigger retrograde responses that influence cell proteostasis in general and AD proteostasis specifically. Potentially pertinent retrograde responses include the mitochondrial unfolded protein response (mtUPR), integrated stress response (ISR), autophagy/mitophagy, and proteasome function. A fuller perspective of mitochondrial dysfunction in AD, and its relation to protein aggregation, could enhance our overall understanding of this disease.
Copyright © 2020. Published by Elsevier Inc.

References

PubMed