Abstract
The hippocampus is one of the earliest and most affected regions in Alzheimer’s disease (AD), followed by the cortex while the cerebellum is largely spared. Importantly, endothelial dysfunction is a common feature of cerebral blood vessels in AD. In this study, we sought to determine if regional heterogeneity of cerebral microvessels might help explain the susceptibility of the hippocampus and cortex as compared to the cerebellum. We isolated microvessels from wild type mice from the cerebellum, cortex, and hippocampus to characterize their vascular phenotype. Superoxide anion was significantly higher in microvessels isolated from the cortex and hippocampus as compared to the cerebellum. Importantly, protein levels of NADPH oxidase (NOX)-2 and NOX-4 were significantly higher in the cortical and hippocampal microvessels as compared to microvessels from the cerebellum. In addition, expression of manganese superoxide dismutase protein was significantly lower in microvessels from the cortex and hippocampus as compared to cerebellum while other antioxidant enzymes were unchanged. There was no difference in eNOS protein expression between the microvessels of the three brain regions; however, bioavailability of tetrahydrobiopterin (BH4), an essential cofactor for eNOS activity, was significantly reduced in microvessels from the hippocampus and cortex as compared to the cerebellum. Higher levels of superoxide and reduced tetrahydrobiopterin bioavailability may help explain the vulnerability of the hippocampus and cortical microvessels to oxidative stress and development of endothelial dysfunction.
Highlights
It is believed that vascular dysfunction may play a role in Alzheimer’s disease (AD)
We have recently demonstrated in endothelial nitric oxide synthase deficient mice, that loss of endothelial nitric oxide (NO) leads to AD-related changes in amyloid precursor protein (APP) and beta-amyloid (Aβ) levels in brain tissue, including the hippocampus [11]
NADPH oxidase (NOX) isoforms are the primary source of superoxide anions in the endothelium [18,19,20]
Summary
It is believed that vascular dysfunction may play a role in Alzheimer’s disease (AD). Cardiovascular and cerebrovascular risk factors, such as midlife hypertension, hypercholesterolemia, diabetes mellitus, obesity, and a sedentary lifestyle as well as stroke are often associated with a higher incidence of AD [1,2]. Cerebrovascular disease is often found in AD [3,4,5]. Blood flow changes and other vascular abnormalities are a common feature of AD [6,7]. Iadecola et al (1999) and Niwa et al (2002) have described endothelial dysfunction as an early event in PLOS ONE | DOI:10.1371/journal.pone.0144062. Iadecola et al (1999) and Niwa et al (2002) have described endothelial dysfunction as an early event in PLOS ONE | DOI:10.1371/journal.pone.0144062 December 2, 2015
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