Noradrenaline activation of neurotrophic pathways protects against neuronal amyloid toxicity.
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-beta (Abeta(1-42) and Abeta(25-35)) toxicity. The noradrenergic co-transmitter galanin was also effective at preventing Abeta-induced cell death. NA inhibited Abeta(25-35)-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 beta(1) and beta(2) 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 Abeta(1-42) and Abeta(25-35) 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 beta adrenoceptor activation of the cAMP response element binding protein pathway.
Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA. scounts@rush.edu
Scott E
SE
Counts
Elliott J
EJ
Mufson
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D004594:Electrophysiology; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D051336:Mitochondrial Membranes / Q000187:drug effects; D020932:Nerve Growth Factor / Q000096:biosynthesis; D009414:Nerve Growth Factors / Q000096:biosynthesis / Q000502:physiology*; D018696:Neuroprotective Agents; D009638:Norepinephrine / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D020917:Receptor, trkA / Q000037:antagonists & inhibitors; D011943:Receptors, Adrenergic, beta / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*
D016229:Amyloid beta-Peptides; D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D011943:Receptors, Adrenergic, beta; D020932:Nerve Growth Factor; D000242:Cyclic AMP; D020917:Receptor, trkA; D020169:Caspases; D009638:Norepinephrine