Mitochondrial Abnormalities in Alzheimer's Disease

TLDR

The finding that oxidative damage in Alzheimer’s disease is largely confined to the cytoplasm of susceptible neurons suggests that mitochondrial abnormalities may be part of the chronic oxidative stress spectrum. The study aimed to determine whether mitochondrial abnormalities exist in Alzheimer’s disease and how they relate to oxidative damage marked by 8‑hydroxyguanosine and nitrotyrosine. The authors used in situ hybridization of mtDNA, immunocytochemistry of cytochrome oxidase, and morphometric analysis of electron micrographs from biopsy specimens to investigate these relationships. Neurons with increased oxidative damage in Alzheimer’s disease exhibit a significant rise in mtDNA and cytochrome oxidase—much of which resides in the cytoplasm and lipofuscin‑associated vacuoles—yet have significantly reduced mitochondria, underscoring an early, intimate link between mitochondrial abnormalities and oxidative damage.

Abstract

The finding that oxidative damage, including that to nucleic acids, in Alzheimer's disease is primarily limited to the cytoplasm of susceptible neuronal populations suggests that mitochondrial abnormalities might be part of the spectrum of chronic oxidative stress of Alzheimer's disease. In this study, we used in situ hybridization to mitochondrial DNA (mtDNA), immunocytochemistry of cytochrome oxidase, and morphometry of electron micrographs of biopsy specimens to determine whether there are mitochondrial abnormalities in Alzheimer's disease and their relationship to oxidative damage marked by 8-hydroxyguanosine and nitrotyrosine. We found that the same neurons showing increased oxidative damage in Alzheimer's disease have a striking and significant increase in mtDNA and cytochrome oxidase. Surprisingly, much of the mtDNA and cytochrome oxidase is found in the neuronal cytoplasm and in the case of mtDNA, the vacuoles associated with lipofuscin. Morphometric analysis showed that mitochondria are significantly reduced in Alzheimer's disease. The relationship shown here between the site and extent of mitochondrial abnormalities and oxidative damage suggests an intimate and early association between these features in Alzheimer's disease.