Title

Noradrenaline activation of neurotrophic pathways protects against neuronal amyloid toxicity

Document Type

Article

Abstract

Degeneration of locus coeruleus (LC) noradrenergic forebrain projection neurons is an early feature of Alzheimer's disease. The physiological consequences of this phenomenon are unclear, but observations correlating LC neuron loss with increased Alzheimer's disease pathology in LC projection sites suggest that noradrenaline (NA) is neuroprotective. To investigate this hypothesis, we determined that NA protected both hNT human neuronal cultures and rat primary hippocampal neurons from amyloid-β (Aβ1-42 and Aβ25-35) toxicity. The noradrenergic co-transmitter galanin was also effective at preventing Aβ-induced cell death. NA inhibited Aβ25-35-mediated increases in intracellular reactive oxygen species, mitochondrial membrane depolarization, and caspase activation in hNT neurons. NA exerted its neuroprotective effects in these cells by stimulating canonical β1 and β2 adrenergic receptor signaling pathways involving the activation of cAMP response element binding protein and the induction of endogenous nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). Treatment with functional blocking antibodies for either NGF or BDNF blocked NA's protective actions against Aβ1-42 and Aβ25-35 toxicity in primary hippocampal and hNT neurons, respectively. Taken together, these data suggest that the neuroprotective effects of noradrenergic LC afferents result from stimulating neurotrophic NGF and BDNF autocrine or paracrine loops via β adrenoceptor activation of the cAMP response element binding protein pathway. © 2010 International Society for Neurochemistry.

Keywords

Alzheimer's disease, Amyloid, Locus coeruleus, Neuroprotection, Neurotrophin, Noradrenaline

Publication Date

5-1-2010

Publication Title

Journal of Neurochemistry

ISSN

00223042

E-ISSN

14714159

Volume

113

Issue

3

First Page

649

Last Page

660

PubMed ID

20132474

Digital Object Identifier (DOI)

10.1111/j.1471-4159.2010.06622.x

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