Correlation Analysis of Capillary APOE, VEGF and eNOS Expression in Alzheimer Brains

Abstract

Vasoactive regulatory and transport proteins can modify the transendothelial blood-brain barrier (BBB) transport of beta-amyloid. Dysfunction of one or more of these proteins is hypothesized to contribute to the pathogenesis of Alzheimer's disease (AD). In this study we investigated superior temporal and occipital cortical sections from ten AD and ten control group brains (CG). They were examined using immunohistochemical techniques staining for β(42) amyloid, APOE, VEGF and eNOS. The densities of senile plaques (SPs) and APOE, VEGF and eNOS positive capillaries in each region and in each AD and CG condition were compared using nonparametric statistical analysis. In the AD cases, there were significant negative correlations between APOE positive capillaries and β(42) amyloid SPs, and positive correlations between APOE positive capillaries and VEGF and eNOS positive capillaries. These results demonstrate the increased presence of APOE activity in AD brain capillaries, and that there is a positive correlation between the expression of APOE and each of VEGF and eNOS in the capillaries of AD brains. It is possible, therefore, that the down regulation of APOE in AD brains may contribute significantly to the pathogenesis of SP lesion development by modulating brain β-amyloid burden. The specific interrelationship between APOE, VEGF and eNOS activity at the BBB requires further investigation.

The role of APOE in cerebrovascular dysfunction

“…In 8 month old male E4FAD mice we have observed characteristics of CV dysfunction including vessels surrounding extracellular Aβ (Fig.2b), CAA (Fig.2c and d), the absence of vessels in areas of high Aβ, and vessel degeneration (Fig.2e). Additional data that apoE modulates the CV include the negative association of APOE positive capillaries and extracellular Aβ plaques, the positive correlation of APOE and expression of angiogenesis/vasoactive mediators (VEGF, eNOS) in AD brain capillaries [89], and the link between apoE levels and CV leakiness in AD patients with small vessel disease [125]. Collectively these data support that APOE4 increases CV leakiness in AD patients compared to APOE3 .…”

Association between low thyroid-stimulating hormone, posterior cortical atrophy and nitro-oxidative stress in elderly patients with cognitive dysfunction

“…These effects are preceded by upregulation of endothelial nitric oxide synthase (eNOS) that enhances nitrosative stress and, in cerebral capillaries, leads to cerebral microvascular degeneration, diminished brain mass, and cerebral functional deficits [ 31 ]. Immunohistochemical studies demonstrated increased activity of endothelial nitric oxide (eNOS) synthesis also in Alzheimer’s diseases in brain capillaries that can lead to cortical atrophy [ 32 ]. An experimental model of hypothyroidism showed that there is increased production of NO in thyroid tissue.…”

“…In accordance with these results and with the results reported in our study, we can support a possible association between increased production of NOx, decreased level of TSH and posterior cortical atrophy (significant correlations between NOx and MMSE just for the whole sample, and between NOx and KS; see Table IV ). Elevated NOx production was associated with obesity in women [ 32 ]. Despite the fact that our results established a significant increased NOx level in women compared with men (and in both groups compared to the control group), the BMIs of women and men did not show significant differences compared with the control group and are in the range of normal values.…”

Apolipoprotein E2 and E3, but Not E4, Promote Retinal Pathologic Neovascularization

“…24 It has been reported that the VEGF level is significantly and positively correlated with the ApoE levels in the retina and choroid of murine eyes and also in the human brain. [24][25][26][27] Because VEGF has been shown to be associated with neovascularization, these findings suggest that ApoE may be related to retinal neovascularization. However, the effects of the ApoEs (e.g., ApoE2, ApoE3, and ApoE4) on retinal neovascularization have not been fully investigated.…”