Amyloid deposition in cerebral vessels (CAA) is a constant feature in A? and non-A? cerebral amyloidosis. Notably, vascular and not parenchymal deposits appear today to be more sensitive predictors of dementia. Unrelated amyloid subunits produce similar lesions in medium/small cerebral vessels and, as often neglected, in capillaries, suggesting common pathogenic mechanisms. To date, it is neither clear why specific mutations predominantly associate with cerebrovascular pathology nor understood why the main phenotype for some vasculotropic variants is hemorrhage/ischemic stroke while for others is cognitive impairment. Co-localizing with the amyloid deposits there is also a group of so-called amyloid-associated components, among them markers of cellular stress and inflammation whose role as active key players in the processes of amyloidogenesis and cell toxicity is far from being defined. Complicating the picture, oligomerization/aggnegation but not fibrillization of amyloidogenic peptides appear to be a pre-requisite to exert both, their cytotoxicity and their ability to trigger an inflammatory response. Although these effects are partially studied in neurons and glial cells, little is known about these mechanisms in the cells forming the vessel wall. Intriguing as well is whether the presence of CAA genetic variants exerts enhanced detrimental effects on cell toxicity and differentially alters endothelium properties, e.g. monolayer permeability. We hypothesize that conformational transitions of amyloidogenic peptides are key elements responsible for the pathogenic vascular features characteristic of the CAA including, among others, protein oligomerization and amyloid formation, cell toxicity, complement activation and the induction of inflammation-related mechanisms. Accordingly, oligomeric and fibrillar assemblies of synthetic A? variants in the presence and absence of selected amyloid associated components will be tested for their ability to induce a cytotoxic effect on cerebral endothelial and smooth-muscle cells and elicit concomitant permeability alterations in endothelial monolayers (aiml) as well as to trigger complement activation and the release of vascular and glial inflammatory components which, in turn, may worsen the toxic phenotype (aim 2). When feasible, results will be validated with similar assemblies extracted from well typified CAA/AD cases. Whether or not specific membrane receptors / binding molecules are mediators of the cellular responses will be explored in aim 3.
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