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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1909.)
© 2009 American Heart Association, Inc.

Cell Biology/Signaling

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

Shin-ichiro Hayashi; Naoyuki Sato; Akitsugu Yamamoto; Yuka Ikegame; Shigeru Nakashima; Toshio Ogihara; Ryuichi Morishita

From the Department of Cell Signaling (S.-i.H., Y.I., S.S.), Gifu University Graduate School of Medicine, Japan; the Department of Clinical Gene Therapy (N.S., R.M.), Osaka Graduate School of Medicine, Japan; the Nagahama Institute of Bioscience and Technology (A.Y.), Japan; and the Department of Geriatric Medicine (S.-i.H., T.O.), Osaka University Graduate School of Medicine, Japan.

Correspondence to Shin-ichiro Hayashi, Department of Cell Signaling, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan. E-mail shin559182{at}aol.com

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 β-amyloid (Aβ), Aβ40, 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, Aβ40 inhibited ex vivo hippocampal revascularization, reendothelialization, and the differentiation of adult endothelial progenitor cells. Importantly, Aβ40 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 Aβ40 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 Aβ40-induced endothelial autophagy and impairment of neurovascular regeneration, suggesting important implications for therapeutic approaches to AD.

The cause and progression of AD still remains unclear. Our present findings indicate that the initial progression of AD might be in part driven by Aβ40-induced phenotypic alterations in neurovascular endothelium with induction of endothelial autophagy and impairment of neurovascular regeneration, suggesting important implications for therapeutic approaches to AD.

Key Words: amyloid • autophagy • cerebrovascular disorders • endothelium