Alzheimer disease-associated peptide, amyloid beta40, 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.


RESULTS
We found that vascular beta-amyloid (Abeta), Abeta40, 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, Abeta40 inhibited ex vivo hippocampal revascularization, reendothelialization, and the differentiation of adult endothelial progenitor cells. Importantly, Abeta40 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 Abeta40 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 Abeta40-induced endothelial autophagy and impairment of neurovascular regeneration, suggesting important implications for therapeutic approaches to AD.
Hayashi
Shin-ichiro
S
Department of Cell Signaling, Gifu University Graduate School of Medicine, Gifu, Japan. shin559182@aol.com
Sato
Naoyuki
N
Yamamoto
Akitsugu
A
Ikegame
Yuka
Y
Nakashima
Shigeru
S
Ogihara
Toshio
T
Morishita
Ryuichi
R
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D001808:Blood Vessels / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D010446:Peptide Fragments / Q000378:metabolism*; D011336:Probability; D012038:Regeneration / Q000502:physiology*; D014162:Transfection
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C090308:amyloid beta-protein (40-1)