Immunohistochemical Markers of Mitochondrial Electron Transport Chain Instability in Human Brain Regions: A Study of Aging and Alzheimer's Disease.

Expanding research indicates that oxidative stress, particularly mitochondrial oxidative stress, is one of the key components in the pathogenesis of Alzheimer's disease (AD). Mitochondrial oxidative stress is largely driven by impaired function of electron transport chain (ETC) complexes and their regulators. This study conducted an immunohistochemical analysis of ETC proteins (α-subunit of complex V, subunits MTCO1 and MTCO2 of complex IV) and mitochondrial complex V inhibitor IF-1 in the neurons of the caudate nucleus head, hippocampus, anterior cingulate gyrus, middle frontal gyrus, and inferior parietal lobule using autopsy material from patients with sporadic AD. Comparisons were made with similar brain regions in autopsy material from age-matched elderly patients and young patients. The results revealed a pattern of ETC impairment in AD fundamentally distinct from that observed in physiological aging. Specifically, a hippocampus-specific failure of the adaptive response was identified: unlike other brain regions, compensatory upregulation of ATP synthase does not occur here despite critical reduction in the protective protein IF-1, directly explaining the heightened vulnerability of hippocampal neurons to damage. Our data deepen the understanding of AD pathogenesis by highlighting region-specific mitochondrial defects as promising targets for tailored therapeutic intervention.