Affiliations: [a] Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA | [b] Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
Correspondence:
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Correspondence to: David Weinshenker, Department of Human Genetics, Emory University School of Medicine, Whitehead 301, 615 Michael St., Atlanta, GA 30322, USA. Tel.: +1 404 727 3106; Fax: +1 404 727 3949; E-mail: dweinsh@emory.edu and Keqiang Ye, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Whitehead 145, 615 Michael St., Atlanta, GA 30322, USA. Tel.: +1 404 712 2814; Fax: +1 404 712 2979; E-mail: kye@emory.edu.
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.
Keywords: Alzheimer's disease, amyloid-β, brain-derived neurotrophic factor, locus coeruleus, neuroprotection, norepinephrine, tropomyosin-related kinase B
