Amyloid β Peptide-(1-42) Induces Internalization and Degradation of β2 Adrenergic Receptors in Prefrontal Cortical Neurons

Emerging evidence indicates that amyloid beta peptide (A beta) initially induces subtle alterations in synaptic function in Alzheimer disease. We have recently shown that A beta binds to beta(2) adrenergic receptor (beta(2)AR) and activates protein kinase A (PKA) signaling for glutamatergic regulation of synaptic activities. Here we show that in the cerebrums of mice expressing human familial mutant presenilin 1 and amyloid precursor protein genes, the levels of beta(2)AR are drastically reduced. Moreover, A beta induces internalization of transfected human beta(2)AR in fibroblasts and endogenous beta(2)AR in primary prefrontal cortical neurons. In fibroblasts, A beta treatment also induces transportation of beta(2)AR into lysosome, and prolonged A beta treatment causes beta(2)AR degradation. The A beta-induced beta(2)AR internalization requires the N terminus of the receptor containing the peptide binding sites and phosphorylation of beta(2)AR by G protein-coupled receptor kinase, not by PKA. However, the G protein-coupled receptor kinase phosphorylation of beta(2)AR and the receptor internalization are much slower than that induced by beta AR agonist isoproterenol. The A beta-induced beta(2)AR internalization is also dependent on adaptor protein arrestin 3 and GTPase dynamin, but not arrestin 2. Functionally, pretreatment of primary prefrontal cortical neurons with A beta induces desensitization of beta(2)AR, which leads to attenuated response to subsequent stimulation with isoproterenol, including decreased cAMP levels, PKA activities, PKA phosphorylation of serine 845 on alpha-amino-2,3-di-hydro-5-methyl-3-oxo-4-isoxazolepropanoic acid (AMPA) receptor subunit 1 (GluR1), and AMPA receptor-mediated miniature excitatory postsynaptic currents. This study indicates that A beta induces beta(2)AR internalization and degradation leading to impairment of adrenergic and glutamatergic activities.