Alzheimer Disease-Associated Peptide, Amyloid β40, Inhibits Vascular Regeneration With Induction of Endothelial Autophagy

Objective-Although the majority of cases of Alzheimer disease ( AD) are known to be attributable to the sporadic (nongenetic) form of the disease, the mechanism underlying its cause and progression still remains unclear. Methods and Results-We found that vascular beta-amyloid (A beta), A beta 40, inhibited the proliferative activity of human brain vascular endothelial cells (HBECs) without toxic effects on them. This peptide also inhibited tube formation and migration of HBECs. Moreover, A beta 40 inhibited ex vivo hippocampal revascularization, reendothelialization, and the differentiation of adult endothelial progenitor cells. Importantly, A beta 40 suppressed the proliferative activity of HBECs through the induction of "self-digesting" autophagy. This induction involved the intracellular regulation of class 3 phosphatidylinositol 3-kinase (PI3K) as well as Akt signaling in HBECs. Furthermore, tissue culture of murine brain sections from GFP-LC3 transgenic mice revealed that A beta 40 not only reduced the vessel density in hippocampal lesions, but also induced autophagy in neurovascular ECs. Conclusions-Our present findings indicate that the initial progression of AD might be in part driven by A beta 40-induced endothelial autophagy and impairment of neurovascular regeneration, suggesting important implications for therapeutic approaches to AD. (Arterioscler Thromb Vasc Biol. 2009; 29:1909-1915.)