Amyloid-ß peptides activate α1-adrenergic cardiovascular receptors.

Alzheimer disease features amyloid-ß (Aß) peptide deposition in brain and blood vessels and is associated with hypertension. Aß peptide can cause vasoconstriction and endothelial dysfunction. We observed that Aß peptides exert a chronotropic effect in neonatal cardiomyocytes, similar to α1-adrenergic receptor autoantibodies that we described earlier. Recently, it was shown that α1-adrenergic receptor could impair blood-brain flow. We hypothesized that Aß peptides might elicit a signal transduction pathway in vascular cells, induced by α1-adrenergic receptor activation. Aß (25-35) and Aß (10-35) induced a positive chronotropic effect in the cardiac contraction assay (28.75±1.15 and 29.40±0.98 bpm), which was attenuated by α1-adrenergic receptor blockers (urapidil, 1.53±1.17 bpm; prazosin, 0.30±0.96 bpm). Both Aß peptides induced an intracellular calcium release in vascular smooth muscle cells. Chronotropic activity and calcium response elicited by Aß (25-35) were blocked with peptides corresponding to the first extracellular loop of the α1-adrenergic receptor. We observed an induction of extracellular-regulated kinase 1/2 phosphorylation by Aß (25-35) in Chinese hamster ovary cells overexpressing α1-adrenergic receptor, vascular smooth muscle cells, and cardiomyocytes. We generated an activation-state-sensitive α1-adrenergic receptor antibody and visualized activation of the α1-adrenergic receptor by Aß peptide. Aß (25-35) induced vasoconstriction of mouse aortic rings and in coronary arteries in Langendorff-perfused rat hearts that resulted in decreased coronary flow. Both effects could be reversed by α1-adrenergic receptor blockade. Our data are relevant to the association between Alzheimer disease and hypertension. They may explain impairment of vascular responses by Aß and could have therapeutic implications.