Soluble amyloid-β, effect on cerebral arteriolar regulation and vascular cells

Background: Evidence indicates that soluble forms of amyloid-beta (A beta) are vasoactive, which may contribute to cerebrovascular dysfunction noted in patients with Alzheimer's Disease and cerebral amyloid angiopathy. The effects of soluble A beta on penetrating cerebral arterioles - the vessels most responsible for controlling cerebrovascular resistance - have not been studied. Results: Freshly dissolved A beta(1-40) and A beta(1-42), but not the reverse peptide A beta(40-1) constricted isolated rat penetrating arterioles and diminished dilation to adenosine tri-phosphate (ATP). A beta(1-42) also enhanced ATP-induced vessel constriction. A beta(1-40) diminished arteriolar myogenic response, and an anti-A beta antibody reduced A beta(1-40) induced arteriolar constriction. Prolonged A beta exposure in vessels of Tg2576 mice resulted in a marked age-dependent effect on ATP-induced vascular responses. Vessels from 6 month old Tg2576 mice had reduced vascular responses whereas these were absent from 12 month old animals. A beta(1-40) and A beta(1-42) acutely increased production of reactive oxygen species (ROS) in cultured rat cerebro-microvascular cells. The radical scavenger MnTBAP attenuated this A beta-induced oxidative stress and A beta(1-40)-induced constriction in rat arterioles. Conclusions: Our results suggest that soluble A beta(1-40) and A beta(1-42) directly affect the vasomotor regulation of isolated rodent penetrating arterioles, and that ROS partially mediate these effects. Once insoluble A beta deposits are present, arteriolar reactivity is greatly diminished.