Abeta42 generation is toxic to endothelial cells and inhibits eNOS function through an Akt/GSK-3beta signaling-dependent mechanism.
The application of beta-amyloid (Abeta) is cytotoxic to endothelial cells, promotes vasoconstriction and impairs nitric oxide (NO) generation or action. However, there is no information on the effect of intracellular Abeta on endothelial cell biology, although recent studies indicate that neuronal Abeta drives Alzheimer's disease pathogenesis. Since the serine-threonine kinase Akt is crucial to both neuronal and endothelial cell survival as well as eNOS activation, we investigated the effects of Abeta expression on Akt-signaling in cultured endothelial cells. Virally-encoded Abeta42 was proapoptotic and inhibitory to Akt phosphorylation in human umbilical vein endothelial cells (HUVECs). Toxicity was characterized by mitochondrial dysfunction, DNA condensation and activation of caspase-3. Substrates downstream of Akt action, GSK-3beta and eNOS, are underphosphorylated in the presence of Abeta. Constitutive activation of Akt reversed Abeta-induced toxicity and stimulated caspase-3 activity, suggesting that inhibition of Akt signaling is functionally significant. These Abeta effects were mediated, in part, through the derepression of GSK-3beta activation and correlated with reductions in NO production. We conclude that intracellular production of Abeta42 is cytotoxic to endothelial cells and that disruption of the Akt/GSK-3beta cell signaling pathway is involved.
Suhara
Toshimitsu
T
Divisions of Neurology and Cardiovascular Research, St Elizabeth's Medical Center, Tufts University, Boston, MA 02135, USA.
Magrané
Jordi
J
Rosen
Kenneth
K
Christensen
Rial
R
Kim
Hyo-Soo
HS
Zheng
Bing
B
McPhie
Donna L
DL
Walsh
Kenneth
K
Querfurth
Henry
H
D000077329:Agammaglobulinaemia Tyrosine Kinase; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D038341:Glycogen Synthase Kinases / Q000378:metabolism*; D006801:Humans; D007424:Intracellular Fluid; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D010446:Peptide Fragments / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D015290:Second Messenger Systems / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D019076:Transgenes / Q000235:genetics; D014471:Umbilical Veins
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D019001:Nitric Oxide Synthase; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; D038341:Glycogen Synthase Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases