title: Ear2 deletion causes early memory and learning deficits in APP/PS1 mice.
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.
authors: Department of Neurology, Clinical Neurosciences Unit, University of Bonn, 53127 Bonn, Germany.
authors: Markus P
authors: MP
authors: Kummer
authors: Department of Neurology, Clinical Neurosciences Unit, University of Bonn, 53127 Bonn, Germany, Institute of Physiology I, Westfälische Wilhelms-University Münster, 48149 Münster, Germany.
authors: Thea
authors: T
authors: Hammerschmidt
authors: Genes and Behavior Department, Max Planck Institute of Biophysical Chemistry, 37077 Göttingen, Germany.
authors: Ana
authors: A
authors: Martinez
authors: Department of Neurology, Clinical Neurosciences Unit, University of Bonn, 53127 Bonn, Germany.
authors: Dick
authors: D
authors: Terwel
authors: Genes and Behavior Department, Max Planck Institute of Biophysical Chemistry, 37077 Göttingen, Germany.
authors: Gregor
authors: G
authors: Eichele
authors: Leibniz-Institut für Arterioskleroseforschung, Genetische Epidemiologie vaskulärer Erkrankungen, 48149 Münster, Germany.
authors: Anika
authors: A
authors: Witten
authors: Leibniz-Institut für Arterioskleroseforschung, Genetische Epidemiologie vaskulärer Erkrankungen, 48149 Münster, Germany.
authors: Stefanie
authors: S
authors: Figura
authors: Leibniz-Institut für Arterioskleroseforschung, Genetische Epidemiologie vaskulärer Erkrankungen, 48149 Münster, Germany.
authors: Monika
authors: M
authors: Stoll
authors: Department of Neurology, Clinical Neurosciences Unit, University of Bonn, 53127 Bonn, Germany.
authors: Stephanie
authors: S
authors: Schwartz
authors: Institute of Physiology I, Westfälische Wilhelms-University Münster, 48149 Münster, Germany.
authors: Hans-Christian
authors: HC
authors: Pape
authors: LIMES Institute, Genomics and Immunoregulation, University of Bonn, 53115 Bonn, Germany.
authors: Joachim L
authors: JL
authors: Schultze
authors: Department of Human Genetics, Emory University, Atlanta, Georgia 30322, and.
authors: David
authors: D
authors: Weinshenker
authors: 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.
authors: Michael T
authors: MT
authors: Heneka
authors: Max Planck Institute of Biophysical Chemistry
authors: Inga
authors: I
authors: Urban
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D047208:Eosinophil-Derived Neurotoxin / Q000235:genetics / Q000378:metabolism*; D007858:Learning / Q000502:physiology*; D008125:Locus Coeruleus / Q000378:metabolism / Q000473:pathology; D018782:Maze Learning / Q000502:physiology*; D008568:Memory / Q000502:physiology*; D008569:Memory Disorders / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; C121001:NR2B NMDA receptor; D053764:Presenilin-1; D016194:Receptors, N-Methyl-D-Aspartate; C580804:presenilin 1, mouse; C479821:Ear2 protein, mouse; D047208:Eosinophil-Derived Neurotoxin; D009638:Norepinephrine
keywords: Alzheimer; locus ceruleus; memory; neurodegeneration; noradrenaline