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

BACKGROUND: Evidence indicates that soluble forms of amyloid-β (Aβ) are vasoactive, which may contribute to cerebrovascular dysfunction noted in patients with Alzheimer's Disease and cerebral amyloid angiopathy. The effects of soluble Aβ on penetrating cerebral arterioles - the vessels most responsible for controlling cerebrovascular resistance - have not been studied. RESULTS: Freshly dissolved Aβ(1-40 )and Aβ(1-42), but not the reverse peptide Aβ(40-1 )constricted isolated rat penetrating arterioles and diminished dilation to adenosine tri-phosphate (ATP). Aβ(1-42 )also enhanced ATP-induced vessel constriction. Aβ(1-40 )diminished arteriolar myogenic response, and an anti-Aβ antibody reduced Aβ(1-40 )induced arteriolar constriction. Prolonged Aβ 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. Aβ(1-40 )and Aβ(1-42 )acutely increased production of reactive oxygen species (ROS) in cultured rat cerebro-microvascular cells. The radical scavenger MnTBAP attenuated this Aβ-induced oxidative stress and Aβ(1-40)-induced constriction in rat arterioles. CONCLUSIONS: Our results suggest that soluble Aβ(1-40 )and Aβ(1-42 )directly affect the vasomotor regulation of isolated rodent penetrating arterioles, and that ROS partially mediate these effects. Once insoluble Aβ deposits are present, arteriolar reactivity is greatly diminished.