alexa Norepinephrine differentially modulates the innate inflammatory response provoked by amyloid-β peptide via action at β-adrenoceptors and activation of cAMP PKA pathway in human THP-1 macrophages.


Journal of Alzheimers Disease & Parkinsonism

Author(s): Yang JH, Lee EO, Kim SE, Suh YH, Chong YH

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Abstract Evidence indicates that norepinephrine (NE) has antiinflammatory activities and plays a neuroprotective role where inflammatory events contribute to Alzheimer's disease pathology. Here, we evaluated the effects of NE on amyloid beta 1-42 (Aβ1-42)-induced cytotoxicity and proinflammatory cytokine/chemokine secretion, and determined the mechanisms through which NE exerts its actions in human THP-1 macrophages. NE clearly reduced the Aβ1-42-mediated production of the proinflammatory chemokine, monocytic chemotactic protein-1 (MCP-1/CCL2). In contrast to its ability to reduce MCP-1 secretion, NE enhanced the amounts of the proinflammatory cytokine interleukin (IL)-1β secreted from Aβ1-42 treated cells. NE significantly reduced the Aβ1-42-induced cytotoxicity in situations where it contributed to the increased IL-1β and decreased MCP-1 during Aβ1-42 stimulation. The ability of NE to differentially modulate the Aβ1-42-induced immune responses was mediated by β-adrenoceptors, as the aforementioned effects were replicated by the β-adrenoceptor agonist, isoproterenol, and blocked by the β-adrenoceptor antagonist, dl-propranolol. Of note, the NE effects on Aβ1-42-induced responses were mimicked by dbcAMP and forskolin, but significantly blocked by H89, an inhibitor of PKA. Moreover, NE abolished Aβ1-42-mediated decline of CREB phosphorylation. Overall, NE suppresses Aβ1-42-mediated cytotoxicity and MCP-1 secretion, but enhances Aβ-mediated IL-1β secretion through action at β-adrenoceptors, accompanied by activation of cAMP/PKA pathway and CREB in human microglia-like THP-1 cells. Copyright © 2012 Elsevier Inc. All rights reserved. This article was published in Exp Neurol and referenced in Journal of Alzheimers Disease & Parkinsonism

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