RRC ID 11785
Author Hayashi S, Sato N, Yamamoto A, Ikegame Y, Nakashima S, Ogihara T, Morishita R.
Title Alzheimer disease-associated peptide, amyloid beta40, inhibits vascular regeneration with induction of endothelial autophagy.
Journal Arterioscler Thromb Vasc Biol
Abstract 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 (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.
Volume 29(11)
Pages 1909-15
Published 2009-11-1
DOI 10.1161/ATVBAHA.109.188516
PII ATVBAHA.109.188516
PMID 19815818
MeSH Alzheimer Disease / metabolism* Alzheimer Disease / pathology Amyloid beta-Peptides / metabolism* Analysis of Variance Animals Autophagy / physiology* Blood Vessels / physiology Cell Movement / physiology Cell Proliferation Cells, Cultured Disease Progression Endothelium, Vascular / cytology Endothelium, Vascular / metabolism* Hippocampus / cytology Humans Male Mice Mice, Transgenic Models, Animal Peptide Fragments / metabolism* Probability Regeneration / physiology* Transfection
IF 6.604
Times Cited 62
Mice RBRC00806