Ear2 deletion causes early memory and learning deficits in APP/PS1 mice
Creators
- 1. Department of Neurology, Clinical Neurosciences Unit, University of Bonn, 53127 Bonn, Germany
- 2. Department of Neurology, Clinical Neurosciences Unit, University of Bonn, 53127 Bonn, Germany and 2Institute of Physiology I, Westfa¨lische Wilhelms- University Mu¨nster, 48149 Mu¨nster, Germany
- 3. Genes and Behavior Department, Max Planck Institute of Biophysical Chemistry, 37077 Go¨ttingen, Germany
- 4. Leibniz-Institut fu¨r Arterioskleroseforschung, Genetische Epidemiologie vaskula¨rer Erkrankungen, 48149 Mu¨nster, Germany
- 5. 2Institute of Physiology I, Westfa¨lische Wilhelms- University Mu¨nster, 48149 Mu¨nster, Germany
- 6. LIMES Institute, Genomics and Immunoregulation, University of Bonn, 53115 Bonn, Germany
- 7. Department of Human Genetics, Emory University, Atlanta, Georgia 30322
- 8. Department of Neurology, Clinical Neurosciences Unit, University of Bonn, 53127 Bonn, Germany and German Center for Neurodegenerative Diseases, 53127 Bonn, Germany
Description
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 theNMDA2A 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 -CaMKII and spatial memory performance in APP/PS1 Ear2( / ) mice. These changes were not accompanied by altered APP processing or amyloid peptide (A ) deposition. Thus, early LC degeneration and subsequentNAreduction may contribute to cognitive deficits via CaMKII and NMDA receptor dysfunction independent of A and suggests that NA supplementation could be beneficial in treating AD.
Files
Kummer_JNeurosci_2014-P21.pdf
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(3.2 MB)
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