O4–02–08: Mitochondrial autophagocytosis in Alzheimer disease

Mitochondrial abnormalities are prominent in Alzheimer disease. In this study, we compared localization of two mitochondrial markers, one cytochrome oxidase–1, a protein with lipoic acid, a sulfur–containing cofactor required for the activity of several mitochondrial enzyme complexes. We performed light and electron microscopic analysis, immunoblot and immunoprecipitation assays. We observed that cases of Alzheimer disease presented both increased lipoic acid and cytochrome oxidase–1 immunoreactivity in the cytoplasm when compared with age–matched and young controls. Significantly, lipoic acid differed from cytochrome oxidase–1 in being associated with granular structures in the susceptible neuronal populations in hippocampus and cortex of cases of Alzheimer disease. In marked contrast, the same neuronal populations in control cases, young and age–matched, exhibited only diffuse localization for both markers. However, immunoblots showed that cases of Alzheimer disease present lower lipoic acid content, ∼75 and ∼50 kDa, when compared with young and age–matched controls. Immunoprecipitation results also showed that cases of Alzheimer disease present a lower protein content corresponding to the ∼75 kDa band. This paradox of increased immunoreactivity and reduced proteins was illuminated by ultrastructure analysis that showed lipoic acid immunodecoration was not only localized to mitochondria and cytosol but also in organelles identified as autophagic vacuoles and lipofuscin in samples from cases of Alzheimer disease but not controls. In contrast, cytochrome oxidase–1 immunoreactivity was limited to mitochondria and cytosol. These results indicate that mitochondria are key targets of increased autophagic degradation in Alzheimer disease. Work in the authors' laboratories is supported by the Alzheimer's Association, Philip Morris USA Inc. and Philip Morris International.