Amyloid beta-peptide induces cell monolayer albumin permeability, impairs glucose transport, and induces apoptosis in vascular endothelial cells.
Amyloid beta-peptide (A beta) is deposited as insoluble fibrils in the brain parenchyma and cerebral blood vessels in Alzheimer's disease (AD). In addition to neuronal degeneration, cerebral vascular alterations indicative of damage to vascular endothelial cells and disruption of the blood-brain barrier occur in AD. Here we report that A beta25-35 can impair regulatory functions of endothelial cells (ECs) from porcine pulmonary artery and induce their death. Subtoxic exposures to A beta25-35 induced albumin transfer across EC monolayers and impaired glucose transport into ECs. Cell death induced by A beta25-35 was of an apoptotic form, characterized by DNA condensation and fragmentation, and prevented by inhibitors of macromolecular synthesis and endonucleases. The effects of A beta25-35 were specific because A beta1-40 also induced apoptosis in ECs with the apoptotic cells localized to the microenvironment of A beta1-40 aggregates and because astrocytes did not undergo similar changes after exposure to A beta25-35. Damage and death of ECs induced by A beta25-35 were attenuated by antioxidants, a calcium channel blocker, and a chelator of intracellular calcium, indicating the involvement of free radicals and dysregulation of calcium homeostasis. The data show that A beta induces increased permeability of EC monolayers to macromolecules, impairs glucose transport, and induces apoptosis. If similar mechanisms are operative in vivo, then A beta and other amyloidogenic peptides may be directly involved in vascular EC damage documented in AD and other disorders that involve vascular amyloid accumulation.
Blanc
E M
EM
Sanders Brown Research Center on Aging, University of Kentucky, Lexington 40536-0230, U.S.A.
Toborek
M
M
Mark
R J
RJ
Hennig
B
B
Mattson
M P
MP
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D016923:Cell Death; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D005609:Free Radicals; D005947:Glucose / Q000378:metabolism*; D007425:Intracellular Membranes / Q000378:metabolism; D009994:Osmolar Concentration; D010446:Peptide Fragments / Q000494:pharmacology; D010539:Permeability; D012709:Serum Albumin / Q000493:pharmacokinetics*; D013552:Swine
D016229:Amyloid beta-Peptides; D005609:Free Radicals; D010446:Peptide Fragments; D012709:Serum Albumin; C074636:amyloid beta-protein (25-35); D005947:Glucose; D002118:Calcium