[en] 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.
Disciplines :
Neurology
Author, co-author :
Kummer, Markus P ✱; Department of Neurology, Clinical Neurosciences Unit, University of Bonn, 53127 Bonn, Germany
Hammerschmidt, Thea ✱; Department of Neurology, Clinical Neurosciences Unit, University of Bonn, 53127 Bonn, Germany, Institute of Physiology I, Westfälische Wilhelms-University Münster, 48149 Münster, Germany
Martinez, Ana; Genes and Behavior Department, Max Planck Institute of Biophysical Chemistry, 37077 Göttingen, Germany
Terwel, Dick; Department of Neurology, Clinical Neurosciences Unit, University of Bonn, 53127 Bonn, Germany
Eichele, Gregor; Genes and Behavior Department, Max Planck Institute of Biophysical Chemistry, 37077 Göttingen, Germany
Schwartz, Stephanie; Department of Neurology, Clinical Neurosciences Unit, University of Bonn, 53127 Bonn, Germany
Pape, Hans-Christian; Institute of Physiology I, Westfälische Wilhelms-University Münster, 48149 Münster, Germany
Schultze, Joachim L; LIMES Institute, Genomics and Immunoregulation, University of Bonn, 53115 Bonn, Germany
Weinshenker, David; Department of Human Genetics, Emory University, Atlanta, Georgia 30322, and
HENEKA, Michael ; Department of Neurology, Clinical Neurosciences Unit, University of Bonn, 53127 Bonn, Germany, German Center for Neurodegenerative Diseases, 53127 Bonn, Germany michael.heneka@ukb.uni-bonn.de
Urban, Inga; Max Planck Institute of Biophysical Chemistry
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