The primary pathogenetic role of vascular hypoperfusion, mitochondria failure and oxidative stress in aging and Alzheimer disease

We studied the cellular and subcellular features of vascular lesions, immunoreactivity of vasoactive substances, and mitochondria in brain vascular wall cells and hippocampal neurons from human Alzheimer disease (AD) and animal models that mimic AD. Lesioned vessels with immunopositive staining for AbPP and iNOS, and large, lipid‐laden vacuoles in the cytoplasm of endothelial cells were observed. Mitochondrial abnormalities and lesions were pronounced in microvessels in human AD, YAC, ApoE4 and C57B6/SJL Tg (+) mice, 2‐vessel occluded and non‐occluded aged rats, with and without selective mitochondrial antioxidant (lipoic acid and ALCAR) treatment. In situ hybridization revealed damaged mitochondria in vascular endothelium and in perivascular cells of lesioned microvessels in human AD and rodent models proximal to regions of large amyloid deposition. mtDNA deletions were associated with increased amounts of immunoreactive AbPP, 8OHG and COX but not eNOS; these deletions and expression of oxidative stress markers indicate that energy deficiency and oxidative stress in AD selectively affect the brain vascular tree and vulnerable neurons, which can be ameliorated by selective mitochondrial treatment.