P4‐171: Cerebral hypoperfusion‐induced oxidative stress and mitochondrial failure as initiators of aging and Alzheimer's disease pathology

Cerebral hypoperfusion-induced mitochondrial failure appears to be a key pathogenic factor in the development of age-associated diseases, triggering mild cognitive impairment and eventual conversion to Alzheimer's disease (AD). Mitochondrial integrity is associated with cellular viability. We studied cellular and subcellular features of hippocampal neurons and microvessel mitochondrial lesions, oxidative stress markers and protein immunoreactivity in human AD and animal models that mimic MCI and/or AD. In addition, we studied the effects of dietary antioxidant treatment on neuronal mitochondrial ultrastructure in rats and ApoE4 mice. 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 AβPP, 8-hydroxyguanosine, all three isoforms of nitric oxide synthase (neuronal, inducible and endothelial NOS) and cytochrome c oxidase. Mitochondrial degeneration was analyzed under electron microscopy in young and old rats with and without dietary supplementation of mitochondrial antioxidants (lipoic acid and ALCAR) as well as transgenic mice overexpressing either AβPP or ApoE4. A significantly higher degree of mitochondrial damage was found in neurons and cerebrovascular wall cells in AD and in aged animal models used compared to age-matched controls and non-treated subjects. These abnormalities coexist with overexpression of AβPP and inducible NOS immunoreactivity and amyloid deposition in the same regions which characterize the presence of large, lipid-laden vacuoles in the cytoplasm of endothelial cells. In addition, in situ hybridization revealed deleted mtDNA positive signals in the damaged mitochondria of neurons, vascular endothelium and perivascular cells. We conclude that blocking the underlying oxidative stress stimuli via treatment with selective pharmacological agents such as selective mitochondrial antioxidants, NO precursors and/or suppressors may normalize the actions of endogenous antioxidant systems and vasoactive substances in brain cells.