Amyloid β peptide-(1 - 42) induces internalization and degradation of β 2 adrenergic receptors in prefrontal cortical neurons

Dayong Wang, Eunice Y. Yuen, Yuan Zhou, Zhen Yan, Yang Kevin Xiang

Research output: Contribution to journalArticle

55 Scopus citations

Abstract

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

Original languageEnglish (US)
Pages (from-to)31852-31863
Number of pages12
JournalJournal of Biological Chemistry
Volume286
Issue number36
DOIs
StatePublished - Sep 9 2011
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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