Abstract 482: Amyloid-β Peptides Induce a Signal Transduction via Activation of the α1-Adrenoreceptor in Vsmc and Cardiomyocytes

Abstract

Hypertension is associated with increased risk of Alzheimer disease (AD) that features Amyloid-β peptide (Aβ) deposition in brain (neuritic plaques) and in blood vessels (cerebral amyloid angiopathy). Recently, it was shown by others that Aβ peptides exert a chronotropic effect in neonatal cardiomyocytes, similar to α1-adrenoreceptor autoantibodies (α-AB) as we described earlier. We hypothesized that Aβ peptides elicit a signal transduction pathway in vascular cells, induced by activation of the α1-adrenoreceptor. Aβ peptides (10-35) and (25-35) induced a positive chorontropic effect in the cardiac contraction assay (CCA) after long term activation up to 4 hours (28.84±1.04 bpm and 28.96±1.08 bpm). The effect was attenuated by the α1-receptor blockers urapidil and prazosin (1.72±0.4 bpm and -0.76±1.16 bpm). β1, β2, AT1, or AT2 receptor blockers had no effect on the positive chronotropic effect of Aβ (10-35) and (25-35). Using confocal microscopy and phosphospecific immunoblotting we observed that both peptides induced ERK 1/2 phosphorylation in Chinese hamster ovary (CHO) cells, overexpressing the α1A adrenoreceptor (CHO-α1-AR), but not in wildtype CHO. pERK was also induced in vascular smooth muscle cells (VSMC) and cardiomyocytes. Both Aβ peptides induced an intracellular Ca2+ signal in VSMC. The positive chronotropic response to Aβ (25-35) in the CCA was blocked with a peptide corresponding to the 1st extracellular loop of the α1-AR, the identical epitope to which α1-AB binds. Our data show that Amyloid-β peptides induce a signal transduction cascade via the α1-adrenoreceptor in VSMC and cardiomyocytes. These data might help explain the newly discovered association between hypertension and Alzheimer disease. The role of Aβ peptides in vascular medicine deserves further study.