The possible role of capillary cerebral amyloid angiopathy in Alzheimer lesion development: a regional comparison

Abstract

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.

MRI-visible perivascular space location is associated with Alzheimer's disease independently of amyloid burden

“…As well as being a core neuropathological finding in AD, neurofibrillary tangles have been demonstrated in association with CAA in patients with AD (Jeynes and Provias, 2006), and tau deposits (neurofibrillary tangles and pretangles) have been described in Aβ-related angiitis, an inflammatory form of CAA (Kurian et al, 2012). One study reviewing perivascular hyperphosphorylated tau in patients with AD found higher levels surrounding the CAA affected vessels than the unaffected ones (Williams et al, 2005).…”

The case for blood–brain barrier dysfunction in the pathogenesis of Alzheimer's disease

“…Cerebral amyloid angiopathy (CAA) is considered an important contributor in the pathogenesis of AD (Jeynes and Provias, 2006;Weller et al, 2009;Dickstein et al, 2010). CAA results from the accumulation of Ab within the structure of cerebral vessels or in the perivascular spaces surrounding them.…”

“…CAA results from the accumulation of Ab within the structure of cerebral vessels or in the perivascular spaces surrounding them. The result is therefore an accumulation of Ab in locations that transport it either into or out of the brain parenchyma or in the spaces whose function is to drain Ab into the venous or CSF compartments (Jeynes and Provias, 2006). In particular, capillary CAA (CAA-1) has been considered an important factor in the pathogenesis of sporadic AD.…”

“…In particular, capillary CAA (CAA-1) has been considered an important factor in the pathogenesis of sporadic AD. In this regard, the roles of various transport proteins associated with the BBB, and the endothelium in particular, such as lipoprotein receptor protein (LRP), receptor for advanced glycation end products (RAGE), and P-glycoprotein (P-gp) are the focus of intense investigation (Jeynes and Provias, 2006;Thal et al, 2010).…”

“…The correlation of dementia rating and NFT levels, but not, in all but the very late stages of AD, SPs has been reported (Bierer et al, 1995;Hibbard and McKeel, 1997;Giannakopoulos et al, 1997). However, there are a few studies that suggest a possible pathogenic correlation between NFTs and SPs (Senut et al, 1991;Yilmazer-Hanke and Hanke, 1999;Deane et al, 2004;Jeynes and Provias, 2006). Convincing evidence of whether or not there is a pathogenic corelationship between NFT and SP development remains elusive.…”