Alzheimer's amyloid β heterogeneous species differentially affect brain endothelial cell viability, blood-brain...

Impaired clearance in the Alzheimer's Disease (AD) brain is key in the formation of Aβ parenchymal plaques and cerebrovascular deposits known as cerebral amyloid angiopathy (CAA), present in >80% of AD patients and ~50% of non-AD elderly subjects. Aβ deposits are highly heterogeneous, containing multiple fragments mostly derived from catabolism of Aβ40/Aβ42, which exhibit dissimilar aggregation properties. Remarkably, the role of these physiologically relevant Aβ species in cerebrovascular injury and their impact in vascular pathology is unknown. We sought to understand how heterogeneous Aβ species affect cerebral endothelial health and assess whether their diverse effects are associated with the peptides aggregation propensities. We analyzed cerebral microvascular endothelial cell (CMEC) viability, blood-brain barrier (BBB) permeability, and angiogenesis, all relevant aspects of brain microvascular dysfunction. We found that Aβ peptides and fragments exerted differential effects on cerebrovascular pathology. Peptides forming mostly oligomeric structures induced CMEC apoptosis, whereas fibrillar aggregates increased BBB permeability without apoptotic effects. Interestingly, all Aβ species tested inhibited angiogenesis in vitro. These data link the biological effects of the heterogeneous Aβ peptides to their primary structure and aggregation, strongly suggesting that the composition of amyloid deposits influences clinical aspects of the AD vascular pathology. As the presence of predominant oligomeric structures in proximity of the vessel walls may lead to CMEC death and induction of microhemorrhages, fibrillar amyloid is likely responsible for increased BBB permeability and associated neurovascular dysfunction. These results have the potential to unveil more specific therapeutic targets and clarify the multifactorial nature of AD.