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
Recommended Citation
Counts, Scott E. and Mufson, Elliott J., "Noradrenaline activation of neurotrophic pathways protects against neuronal amyloid toxicity" (2010). Translational Neuroscience. 1906.
https://scholar.barrowneuro.org/neurobiology/1906