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 (A D). In addition to neuronal degeneration, cerebral vascular alteration s indicative of damage to vascular endothelial cells and disruption of the blood-brain barrier occur in AD. Here we report that A beta 25-35 can impair regulatory functions of endothelial cells (ECs) from porci ne pulmonary artery and induce their death. Subtoxic exposures to A be ta 25-35 induced albumin transfer across EC monolayers and impaired gl ucose transport into ECs. Cell death induced by A beta 25-35 was of an apoptotic form, characterized by DNA condensation and fragmentation, and prevented by inhibitors of macromolecular synthesis and endonuclea ses. The effects of A beta 25-35 were specific because A beta 1-40 als o induced apoptosis in ECs with the apoptotic cells localized to the m icroenvironment of A beta 1-40 aggregates and because astrocytes did n ot undergo similar changes after exposure to A beta 25-35. Damage and death of ECs induced by A beta 25-35 were attenuated by antioxidants, a calcium channel blocker, and a chelator of intracellular calcium, in dicating 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 in duces apoptosis. If similar mechanisms are operative in vivo, then AP and other amyloidogenic peptides may be directly involved in vascular EC damage documented in AD and other disorders that involve vascular a myloid accumulation.