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: Markus P Kummer, Thea Hammerschmidt, Ana Martinez, Dick Terwel, Gregor Eichele, Anika Witten, Stefanie Figura, Monika Stoll, Stephanie Schwartz, Hans-Christian Pape, Joachim L Schultze, David Weinshenker, Michael T Heneka, Inga Urban
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 34 Issue 26 Pg. 8845-54 (Jun 25 2014) ISSN: 1529-2401 [Electronic] United States
• PMID: 24966384 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 the authors 0270-6474/14/348845-10$15.00/0.

Chemical References

• Amyloid beta-Protein Precursor
• NR2B NMDA receptor
• Presenilin-1
• Receptors, N-Methyl-D-Aspartate
• presenilin 1, mouse
• Ear2 protein, mouse
• Eosinophil-Derived Neurotoxin
• Norepinephrine

Topics

• Amyloid beta-Protein Precursor (genetics, metabolism)
• Animals
• Eosinophil-Derived Neurotoxin (genetics, metabolism)
• Learning (physiology)
• Locus Coeruleus (metabolism, pathology)
• Maze Learning (physiology)
• Memory (physiology)
• Memory Disorders (genetics, metabolism)
• Mice
• Mice, Knockout
• Mice, Transgenic
• Nerve Degeneration (genetics, metabolism, pathology)
• Neurons (metabolism)
• Norepinephrine (metabolism)
• Presenilin-1 (genetics, metabolism)
• Receptors, N-Methyl-D-Aspartate (genetics, metabolism)