Amyloid-β Peptides Activate α1-Adrenergic Cardiovascular Receptors

Alzheimer disease features amyloid- (A) peptide deposition in brain and blood vessels and is associated with hypertension. A peptide can cause vasoconstriction and endothelial dysfunction. We observed that A peptides exert a chronotropic effect in neonatal cardiomyocytes, similar to (1)-adrenergic receptor autoantibodies that we described earlier. Recently, it was shown that (1)-adrenergic receptor could impair blood-brain flow. We hypothesized that A peptides might elicit a signal transduction pathway in vascular cells, induced by (1)-adrenergic receptor activation. A (25-35) and A (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 (1)-adrenergic receptor blockers (urapidil, 1.53 +/- 1.17 bpm; prazosin, 0.30 +/- 0.96 bpm). Both A peptides induced an intracellular calcium release in vascular smooth muscle cells. Chronotropic activity and calcium response elicited by A (25-35) were blocked with peptides corresponding to the first extracellular loop of the (1)-adrenergic receptor. We observed an induction of extracellular-regulated kinase 1/2 phosphorylation by A (25-35) in Chinese hamster ovary cells overexpressing (1)-adrenergic receptor, vascular smooth muscle cells, and cardiomyocytes. We generated an activation-state-sensitive (1)-adrenergic receptor antibody and visualized activation of the (1)-adrenergic receptor by A peptide. A (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 (1)-adrenergic receptor blockade. Our data are relevant to the association between Alzheimer disease and hypertension. They may explain impairment of vascular responses by A and could have therapeutic implications.