ISOFORM-SPECIFIC VASOCONSTRICTION INDUCED BY APOLIPOPROTEIN-E AND MODULATION OF THIS EFFECT BY ALZHEIMERS BETA-AMYLOID PEPTIDE

A beta peptides are thought to be centrally involved in Alzheimer's di sease (AD) pathogenesis, although A beta's pathophysiological mechanis ms remain to be elucidated. We previously showed that soluble beta-amy loid(1-40) (A beta) and A beta(1-42) exhibit vasoactive properties, an d are able to promote vasoconstriction in rat aortae induced by an end ogenous vasoconstrictor, endothelin-1. It is well established that the APOE epsilon 4 allele confers risk for both familial and sporadic AD, as well as for hypertension. We now report that physiologic amounts ( 10 nM) of specific human recombinant apoE isoforms are vasoactive (E4 > E3, and not E2) in isolated rat aortae. In order to investigate if v arious apoE isoforms could modulate A beta vasoactivity, we co-incubat ed A beta(1-40) with various isoforms of apoE in our tissue bath syste m. Our results show that, while none of the APOE isoforms are able to affect the maximum constriction induced by A beta; the apoE E4 isoform synergistically enhances the rate of vasoconstriction induced by A be ta. Our data suggest that apoE may promote hypertension and contribute to AD pathogenesis via enhancement of vasoconstriction, and support a link between hypertension, cerebral amyloid angiopathy and AD. (C) 19 98 Elsevier Science Ireland Ltd. All rights reserved.