Selective Loss of Noradrenaline Exacerbates Early Cognitive Dysfunction and Synaptic Deficits in APP/PS1 Mice

• Type of Material: Article
• Authors: Thea Hammerschmidt, University of Bonn; Markus P. Kummer, University of Bonn; Dick Terwel, University of Bonn; Ana Martinez, Max Planck Institute of Biophysical Chemistry; Ali Gorji, Westfälische Wilhelms-University Münster; Hans-Christian Pape, Westfälische Wilhelms-University Münster; Karen Rommelfanger, Emory University; Jason Schroeder, Emory University; Monika Stoll, Leibniz-Institut für Arterioskleroseforschung; Joachim Schultze, University of Bonn; David Weinshenker, Emory University; Michael T. Heneka, University of Bonn
• Language: English
• Date: 2013-03-01
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013 Society of Biological Psychiatry.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.biopsych.2012.06.013
• Title of Journal or Parent Work: Biological Psychiatry
• ISSN: 0006-3223
• Volume: 73
• Issue: 5
• Start Page: 454
• End Page: 463
• Grant/Funding Information: This work was supported by grants from the Interdisciplinary Center for Clinical Research (HEN3/003/06) to MTH and H-CP, the Institute for the Study of Aging to DW, and two grants from the Emory University Alzheimer's Disease Research Center (PHS AG025688) to DW.
• Keywords: pathogenesis; Life Sciences & Biomedicine; ALZHEIMERS-DISEASE; degeneration; Neurosciences & Neurology; Alzheimer's disease; SOLUBLE OLIGOMERS; LONG-TERM POTENTIATION; TRANSGENIC MICE; Psychiatry; LOCUS-CERULEUS DEGENERATION; NEUROSCIENCES; ADULT-RAT BRAIN; norepinephrine; NEURONAL LOSS; NEUROTROPHIC FACTOR; PROTEIN-KINASE-II; DOPAMINE-BETA-HYDROXYLASE; noradrenaline; Neurosciences; Science & Technology; PSYCHIATRY, SCI; locus coeruleus; CaMKII; memory
• Research Categories: Biology, Genetics; Biology, Neuroscience; Psychology, Experimental

Abstract

Background: Degeneration of the locus coeruleus (LC), the major noradrenergic nucleus in the brain, occurs early and is ubiquitous in Alzheimer's disease (AD). Experimental lesions to the LC exacerbate AD-like neuropathology and cognitive deficits in several transgenic mouse models of AD. Because the LC contains multiple neuromodulators known to affect amyloid β toxicity and cognitive function, the specific role of noradrenaline (NA) in AD is not well understood. Methods: To determine the consequences of selective NA deficiency in an AD mouse model, we crossed dopamine β-hydroxylase (DBH) knockout mice with amyloid precursor protein (APP)/presenilin-1 (PS1) mice overexpressing mutant APP and PS1. Dopamine β-hydroxylase (-/-) mice are unable to synthesize NA but otherwise have normal LC neurons and co-transmitters. Spatial memory, hippocampal long-term potentiation, and synaptic protein levels were assessed. Results: The modest impairments in spatial memory and hippocampal long-term potentiation displayed by young APP/PS1 or DBH (-/-) single mutant mice were augmented in DBH (-/-)/APP/PS1 double mutant mice. Deficits were associated with reduced levels of total calcium/calmodulin-dependent protein kinase II and N-methyl-D-aspartate receptor 2A and increased N-methyl-D-aspartate receptor 2B levels and were independent of amyloid β accumulation. Spatial memory performance was partly improved by treatment with the NA precursor drug L-threo-dihydroxyphenylserine. Conclusions: These results indicate that early LC degeneration and subsequent NA deficiency in AD may contribute to cognitive deficits via altered levels of calcium/calmodulin-dependent protein kinase II and N-methyl-D-aspartate receptors and suggest that NA supplementation could be beneficial in early AD.