Ear2 Deletion Causes Early Memory and Learning Deficits in APP/PS1 Mice
- Markus P. Kummer1,*,
- Thea Hammerschmidt1,2,*,
- Ana Martinez3,
- Dick Terwel1,
- Gregor Eichele3,
- Anika Witten5,
- Stefanie Figura5,
- Monika Stoll5,
- Stephanie Schwartz1,
- Hans-Christian Pape2,
- Joachim L. Schultze4,
- David Weinshenker6, and
- Michael T. Heneka1,7
- 1Department of Neurology, Clinical Neurosciences Unit, University of Bonn, 53127 Bonn, Germany,
- 2Institute of Physiology I, Westfälische Wilhelms-University Münster, 48149 Münster, Germany,
- 3Genes and Behavior Department, Max Planck Institute of Biophysical Chemistry, 37077 Göttingen, Germany,
- 4LIMES Institute, Genomics and Immunoregulation, University of Bonn, 53115 Bonn, Germany,
- 5Leibniz-Institut für Arterioskleroseforschung, Genetische Epidemiologie vaskulärer Erkrankungen, 48149 Münster, Germany,
- 6Department of Human Genetics, Emory University, Atlanta, Georgia 30322, and
- 7German Center for Neurodegenerative Diseases, 53127 Bonn, Germany
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Author contributions: M.P.K., T.H., D.T., G.E., H.-C.P., J.L.S., D.W., and M.T.H. designed research; M.P.K., T.H., A.M., A.W., S.F., and S.S. performed research; M.P.K., T.H., A.M., D.T., A.W., S.F., and M.S. analyzed data; M.P.K., T.H., D.W., and M.T.H. wrote the paper.
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↵*M.P.K. and T.H. contributed equally to this work.
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.
- Received September 16, 2013.
- Revision received April 3, 2014.
- Accepted April 21, 2014.
- Copyright © 2014 the authors 0270-6474/14/348845-10$15.00/0
