[P‐074]: The primary pathogenetic role of vascular contains vasoactive substances, hypoperfusion, mitochondria failure and oxidative stress in aging and Alzheimer disease

It is controversial whether vascular abnormalities participate as pathogenic factors during the development and maturation of aged-associated diseases that trigger mild cognitive impairment (MCI) and eventual conversion to AD. We studied the cellular and subcellular features of vascular lesions including vascular content, vasoactive substances immunoreactivity and mitochondria in brain vascular wall cells and in hippocampal neurons from human AD and animal models that mimic AD or MCI. In situ hybridization, using mitochondrial DNA (mtDNA) probes for human wild type, 5kb deleted and mouse mtDNA, was performed in conjunction with immunocytochemistry using antibodies against AbPP, 8-hydroxyguanosine (8OHG), all three isoforms of NOS and cytochrome c oxidase (COX). We found a higher degree of amyloid deposition in the vessels with more severe lesions which are immunopositive staining for AbPP and iNOS and possessed large, lipid-laden vacuoles in the cytoplasm of endothelial cells. Significantly more mitochondrial abnormalities were seen in microvessels, where lesions occurred, in human AD specimens, YAC, ApoE4 and C57B6/SJL Tg (+) mice, 2 vessels occluded aged rats and old aged rats without selective mitochondrial antioxidants (Lipoic Acid and ALCAIR) treatment. In situ hybridization, using wild type and chimera (recognizing mtDNA with the 5 kB deletion) mtDNA probes, revealed positive signals in the damaged mitochondria from the vascular endothelium and in perivascular cells of lesioned microvessels in human AD, YAC, ApoE4 and C57B6/SJL Tg (+) mouse and rats subjected to the long term CBH occlusion tissues. This damage was proximal to regions of large amyloid deposition. These mtDNA deletions were associated with increased amounts of immunoreactive AbPP, 8OHG and COX but not eNOS in the same cellular and subcellular compartments. The mtDNA deletion and expression of oxidative stress markers in vascular wall cells of these brains indicates that energy deficiency and oxidative stress, in AD, selectively affects the brain vascular tree and whole populations of vulnerable neurons. Future studies that examine the importance of mitochondrial pathophysiology in different cellular compartments may provide important insight not only into neurodegenerative and/or cerebrovascular disease pathobiology but may provide treatment targets of these conditions.