There is significant evidence to suggest that a damaged or dysfunctional blood-brain barrier (BBB) may contribute to the pathogenesis of Alzheimer's disease (AD) lesions. Lipoprotein receptor-related protein (LRP-1) and receptor for advanced glycation end products (RAGE) are known to be important (BBB) capillary transport proteins. Altered expression of either of these capillary endothelial LRP-1 and RAGE receptor proteins could indicate a dysfunction of the BBB and its transport regulation of beta-amyloid (Abeta). Cortical samples from the superior temporal (ST) and calcarine occipital (COC) cortices of ten confirmed AD brains and ten comparison group (CG) brains were examined. The densities of neurofibrillary tangles (NFTs), senile plaques (SPs) and LRP-1 and RAGE positive capillaries were recorded and statistically analyzed. There was a statistically significant difference between AD and CG cases and the densities of LRP-1 and RAGE positive capillaries, the AD cases demonstrating the greater numbers. Further, in AD brains there were significant negative correlations between the Abeta burden of SPs and both LRP-1 and RAGE-positive capillaries [p < .001]. Additionally, there was a strong positive correlation between LRP-1 and RAGE capillaries in AD brains [p < .001]. These results suggest that alterations in the LRP-1 and RAGE mediated transport of Abeta take place in AD brains in lesion prone regions and may therefore contribute to SP lesion pathogenesis.

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Recent studies have observed beta-amyloid-positive capillaries in lesion-prone regions of Alzheimer's disease (AD) brains. It is possible that there is a pathogenic link between neurofibrillary tangles (NFTs) and/or senile plaques (SPs) and altered capillary structure/function. In this study, we examined and compared brain tissue from a frequently observed NFT abundant area, the superior temporal cortex (ST), and a comparatively much NFT sparser area, the calcarine cortex (COC), in ten AD and ten normal adult control brain samples. We recorded the densities of NFTs, and beta-amyloid(8-17,40,42) peptide forms in SPs, capillaries and large vessels [cerebral amyloid angiopathy (CAA)] in these areas. Our results demonstrated that there was a significant difference between the means of NFT and SP beta(8-17,40) lesions when comparing the ST and COC cortical regions in both AD and control brains. In AD brains, we observed a positive correlation between NFTs and SPs in both regions, and between NFTs and beta-amyloid-positive capillaries and CAA vessels, particularly in the calcarine cortex. In addition, significant correlations were observed between some SP beta-amyloid peptide forms and CAA beta(42), in particular, in both regions. These new observations support the view that there are regional (focal) differences in the presence of each AD lesion, and that there may be a pathogenic relationship between the development of AD lesions and beta-amyloid-positive vessels. The data are also consistent with the concept that a focally dysfunctional blood-brain barrier (BBB) that is unable to regulate the influx/efflux of neurotoxic amyloid peptides may participate in the pathogenesis of AD lesions.

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Alzheimer's disease (AD) is a neurodegenerative disease that leads to a progressive loss of integrative and memory capacities of the brain. This is the predominant form of neurodegenerative dementia, with a growing prevalence of between 1 in 50 and 1 in 100 in North America. Numerous hypotheses related to the etiology of AD have developed over the years. However, among the various published hypotheses, the predominant one is related to the progressive and prominent accumulation of central nervous system β-amyloid peptide and the ensuing brain burden created. It is, therefore, important to consider the homeostatic mechanisms underlying β-amyloid transport dynamics between the brain and blood vascular compartments. As well, there is a dynamic interrelationship between soluble and insoluble forms of the peptide. Factors that underlie and regulate these dynamic processes are likely relevant to the end accumulation of β-amyloid peptide in the brain compartment and ultimately in insoluble forms, which is characteristic of, and significant for, the pathophysiology of the Alzheimer's brain. Significantly, and in particular relation to the amyloid burden theory mentioned above, it has been postulated that a dysfunctioning blood-brain barrier (BBB) may play a significant, if not critical, role in the pathogenesis of AD. By allowing the influx of injurious materials or agents into the brain or by impeding or blocking the efflux of those materials and/or agents, BBB-related neuronopathies and their associated sequelae could, and do, ensue.

The accumulation of beta-amyloid [Aβ] within senile plaques [SP] is characteristic of these lesions in Alzheimer's disease. The accumulation of Aβ 42, in particular, in the superior temporal [ST] cortex may result from an inability of the blood brain barrier (BBB) to regulate the trans-endothelial transport and clearance of the amyloid. Lipoprotein receptor-related protein [LRP] and P-glycoprotein [P-gp] facilitate the efflux of Aβ out of the brain, whereas receptor for advanced glycation end products [RAGE] facilitates Aβ influx. Additionally, vascular endothelial growth factor [VEGF] and endothelial nitric oxide synthase [eNOS] may influence the trans-BBB transport of Aβ. In this study we examined ST samples and compared SP burden of all types with the capillary expression of LRP, p-gp, RAGE, VEGF, and e-NOS in samples from 15 control and 15 Alzheimer brains. LRP, P-gp, RAGE, VEGF, and eNOS positive capillaries and Aβ 42 plaques were quantified and statistical analysis of the nonparametric data was performed using the Mann-Whitney and Kruskal-Wallis tests. In the Alzheimer condition P-gp, VEGF, and eNOS positive capillaries were negatively correlated with SP burden, but LRP and RAGE were positively correlated with SP burden. These results indicate altered BBB function in the pathogenesis of SPs in Alzheimer brains.

OBJECTIVE -To examine the diabetes risk association with femur length, standing height, and height without femur length (HWFL) (HWFL ϭ standing height Ϫ femur length).RESEARCH DESIGN AND METHODS -We used data from three time periods of the National Health and Nutrition Examination Survey (1999 -2000, 2001-2002, and 2003-2004) for this cross-sectional analysis and confined the eligible subjects to 6,188 adults aged 20ϩ years who had fasted Ն8 h and had no missing values of femur length or standing height. The outcome measure was type 2 diabetes. RESULTS

Fifteen Alzheimer (AD) and fifteen normative (NM) age-matched autopsy brains were analyzed in superior temporal cortex, hippocampal and brainstem samples. Vascular endothelial growth factor (VEGF) positive capillaries were quantitatively analyzed in all three sites in the 30 cases. Amyloid β42 senile plaques and VEGF positive capillaries were counted and statistically analyzed using Mann-Whitney, Kruskal-Wallis and the non-parametric Spearman's test. There is a significantly different expression of capillary VEGF between normative and Alzheimer brains. Within Alzheimer's superior temporal, hippocampus and brainstem sites there was reduced VEGF expression, with the P value being less than 0.05 in all three sites (superior temporal less than 0.035, hippocampus less than 0.001, brainstem less than 0.006). As VEGF is an important endothelial growth factor involved in vascular remodeling, angiogenesis, and endothelial/blood brain barrier maintenance, its reduced expression in Alzheimer's disease is evidence for altered capillary function in this disease, which may be contributory to its pathogenesis by altering beta amyloid handling and efflux.