Inhibition of angiogenesis by Abeta peptides.
Abeta peptides are naturally occurring peptides forming beta-sheet aggregates that constitute an integral component of senile plaques and vascular deposits in Alzheimer's disease. Since several peptides adopting a beta-sheet conformation have been shown to be anti-angiogenic, we investigated the effect of Abeta on angiogenesis. We show that in vitro, Abeta dose-dependently inhibits the formation of capillaries by human brain endothelial cells plated on Matrigel and stimulates capillary degeneration at high doses. Preparations of Abeta peptides containing a higher content of beta-sheet structures are more potently anti-angiogenic in vitro. Ex vivo, Abeta dose-dependently opposes angiogenesis in rat aortae and in human middle cerebral arteries. In vivo, Abeta dose dependently inhibits angiogenesis in the chick chorioallantoic membrane assay and suppresses bFGF-induced blood vessel formation in the corneal micropocket and Matrigel plug assays. Since angiogenesis is required for tumor growth, we explored the effect of Abeta on human glioblastoma (U87MG) and human lung adenocarcinoma (A549) tumors. We show that intra-tumoral injection of Abeta potently inhibits the growth and vascularization of human glioblastoma and human lung adenocarcinoma tumor xenografts in nude mice. Similarly to the intra-tumoral injection regimen, Abeta delivered intraperitoneally also suppressed the growth of human lung adenocarcinoma tumor xenografts. Altogether our data show that Abeta is an angiogenesis inhibitor.
Paris
Daniel
D
The Roskamp Institute, Sarasota, Florida 34243, USA.
Townsend
Kirk
K
Quadros
Amita
A
Humphrey
James
J
Sun
Jiazhi
J
Brem
Steven
S
Wotoczek-Obadia
Marguerite
M
DelleDonne
Anthony
A
Patel
Nikunj
N
Obregon
Demian F
DF
Crescentini
Robert
R
Abdullah
Laila
L
Coppola
Domenico
D
Rojiani
Amyn M
AM
Crawford
Fiona
F
Sebti
Saïd M
SM
Mullan
Michael
M
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D020768:Middle Cerebral Artery / Q000166:cytology; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000517:prevention & control; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010446:Peptide Fragments / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D016896:Treatment Outcome
D016229:Amyloid beta-Peptides; D020533:Angiogenesis Inhibitors; D010446:Peptide Fragments