Norepinephrine Protects against Amyloid-beta Toxicity via TrkB

• Type of Material: Article
• Authors: Xia Liu, Emory University; Keqiang Ye, Emory University; David Weinshenker, Emory University
• Language: English
• Date: 2015-01-01
• Publisher: IOS Press
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2015-IOS Press and the authors. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.3233/JAD-141062
• Title of Journal or Parent Work: Journal of Alzheimer's Disease
• ISSN: 1387-2877
• Volume: 44
• Issue: 1
• Start Page: 251
• End Page: 260
• Grant/Funding Information: This work was funded by the National Institutes of Health (AG025688 to DW and KY, DC010204 to KY).
• Keywords: Neurosciences & Neurology; Alzheimer's disease; tropomyosin-related kinase B; Science & Technology; MEMORY DEFICITS; BRAIN; BDNF; Neurosciences; norepinephrine; locus coeruleus; NEURONS; neuroprotection; NEUROTROPHIC FACTOR; Life Sciences & Biomedicine; MOUSE MODEL; ALZHEIMERS-DISEASE; OXIDATIVE STRESS; brain-derived neurotrophic factor; LOCUS-CERULEUS; amyloid-beta; TRANSGENIC MOUSE
• Research Categories: Health Sciences, Pathology; Biology, Neuroscience

Abstract

The locus coeruleus (LC), the brainstem noradrenergic nucleus that is the sole source of norepinephrine (NE) in the forebrain, is one of the first structures affected in Alzheimer's disease (AD). Experimental ablation of the LC exacerbates, while increasing NE abates, AD-like neuropathology and cognitive deficits in animal models of the disease. Some neuroprotective effects of NE appear to be mediated by tropomyosin-related kinase B (TrkB), the canonical receptor for brain-derived neurotrophic factor (BDNF). Here, we report that NE dose-dependently protected primary cortical and LC neurons from amyloid-β (Aβ) toxicity. The neuroprotective effects of NE were fully prevented by the Trk receptor antagonist K252a but only partially attenuated by adrenergic receptor antagonists and not mimicked by adrenergic agonists. Activation of TrkB by NE in cortical and LC neurons was confirmed by immunoblot and immunocytochemistry for phospho-TrkB. These results indicate that NE can activate TrkB and protect against Aβ toxicity, at least in part, via adrenergic receptor-independent mechanisms, and have implications for the consequences of LC degeneration in AD and potential therapies for the disease.