Ear2 deletion causes early memory and learning deficits in APP/PS1 mice

J Neurosci. 2014 Jun 25;34(26):8845-54. doi: 10.1523/JNEUROSCI.4027-13.2014.

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.

Keywords: Alzheimer; locus ceruleus; memory; neurodegeneration; noradrenaline.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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