Ear2 Deletion Causes Early Memory and Learning Deficits in APP/PS1 Mice

• Type of Material: Article
• Authors: Markus P. Kummer, University of Bonn; Thea Hammerschmidt, University of Bonn; Ana Martinez, Max Planck Institute of Biophysical Chemistry; Dick Terwel, University of Bonn; Gregor Eichele, Max Planck Institute of Biophysical Chemistry; Anika Witten, Leibniz-Institut für Arterioskleroseforschung; Stefanie Figura, Leibniz-Institut für Arterioskleroseforschung; Monika Stoll, Leibniz-Institut für Arterioskleroseforschung; Stephanie Schwartz, University of Bonn; Hans-Christian Pape, Westfälische Wilhelms-University Münster; Joachim L. Schultze, University of Bonn; David Weinshenker, Emory University; Michael T. Heneka, University of Bonn
• Language: English
• Date: 2014-06-25
• Publisher: Society for Neuroscience
• Publication Version: Final Published Version
• Copyright Statement: © 2014 the authors.
• License: Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1523/JNEUROSCI.4027-13.2014
• Title of Journal or Parent Work: Journal of Neuroscience
• ISSN: 0270-6474
• Volume: 34
• Issue: 26
• Start Page: 8845
• End Page: 8854
• Grant/Funding Information: This work was supported by grants from the INMiND project and the Cluster of Excellence “ImmunoSensation” to M.T.H., the Interdisciplinary Center of Clinical Research (IZKF; HEN3/003/06) to M.T.H. and H.-C.P., the Institute for the Study of Aging to D.W., and a pilot grant from the Emory University Alzheimer's Disease Research Center (PHS AG025688) to D.W.
• Keywords: NUCLEUS BASALIS; MECHANISMS; ALZHEIMERS-DISEASE; noradrenaline; LOCUS-COERULEUS; Science & Technology; DEGENERATION; PROTEIN-KINASE-II; NEUROSCIENCES; NOREPINEPHRINE; EXPRESSION; Alzheimer; NEURONAL LOSS; TRANSGENIC MICE; locus ceruleus; Neurosciences; Life Sciences & Biomedicine; memory; Neurosciences & Neurology; neurodegeneration
• Research Categories: Biology, Physiology; Biology, Genetics

Abstract

To assess the consequences of locus ceruleus (LC) degeneration and subsequent noradrenaline (NA) deficiency in early Alzheimer's disease (AD), mice overexpressing mutant amyloid precursor protein and presenilin-1 (APP/PS1) were crossed with Ear2(-/-) mice that have a severe loss of LC neurons projecting to the hippocampus and neocortex. Testing spatial memory and hippocampal long-term potentiation revealed an impairment in APP/PS1 Ear2(-/-) mice, whereas APP/PS1 or Ear2(-/-) mice showed only minor changes. These deficits were associated with distinct synaptic changes including reduced expression of the NMDA 2A subunit and increased levels of NMDA receptor 2B in APP/PS1 Ear2(-/-) mice. Acute pharmacological replacement of NA by L-threo-DOPS partially restored phosphorylation of β-CaMKII and spatial memory performance in APP/PS1 Ear2(-/-) mice. These changes were not accompanied by altered APP processing or amyloid β peptide (Aβ) deposition. Thus, early LC degeneration and subsequent NA reduction may contribute to cognitive deficits via CaMKII and NMDA receptor dysfunction independent of Aβ and suggests that NA supplementation could be beneficial in treating AD.