Atherosclerotic lesions and mitochondrial dna deletions as a primary hallmark of the brain microcirculation - Implication in the pathogenesis of Alzheimer's disease

The pathogenesis that is primarily responsible for Alzheimer's disease (AD) and cerebrovascular accidents (CVA) appears to involve chronic hypoperfusion-induced mitochondrial lesions. We studied the ultrastructural features of vascular lesions and mitochondria in brain vascular wall cells from human AD biopsy samples and two transgenic mouse models of AD, yeast artificial chromosome (YAC), and C57B6/SJL transgenic positive (Tg+), which overexpress human amyloid beta precursor protein (AβPP). In situ hybridization using probes for normal and 5 Δkb-deleted human and mouse mitochondrial DNA (mtDNA) was performed along with immunocytochemistry using antibodies against the Aβ peptide processed from AβPP, 8-hydroxy-2′-deoxyguanosine (8OHG), and cytochrome C oxidase (COX). More amyloid deposition, oxidative stress markers as well as mitochondrial DNA deletions, and structural abnormalities were present in the vascular walls of the human AD samples and the AβPP-YAC and C57B6/SJL Tg (+) transgenic mice compared to age-matched controls. Ultrastructural damage in perivascular cells highly correlated with endothelial lesions in all samples. Therefore, pharmacological interventions, directed at correcting the chronic hypoperfusion state, may change the natural course of the development of dementing neurodegeneration.