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.