科研之友
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摘要
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.
- 出版日期2011-9-9
