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Author Notes:

Correspondence should be addressed to Dr. Michael T. Heneka, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany. michael.heneka@ukb.uni-bonn.de

M.P.K., T.H., D.T., G.E., H.-C.P., J.L.S., D.W., and M.T.H. designed research; M.P.K., T.H., A.M., A.W., S.F., and S.S. performed research; M.P.K., T.H., A.M., D.T., A.W., S.F., and M.S. analyzed data; M.P.K., T.H., D.W., and M.T.H. wrote the paper.

We thank the Dainippon Sumitomo Pharmaceutical Company for the generous gift of l-threo DOPS

We also thank C. Jerome and C. Hülsmann for excellent technical assistance.

The authors declare no competing financial interests.

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Research Funding:

This work was supported by grants from the INMiND project and the Cluster of Excellence “ImmunoSensation” to M.T.H., the Interdisciplinary Center of Clinical Research (IZKF; HEN3/003/06) to M.T.H. and H.-C.P., the Institute for the Study of Aging to D.W., and a pilot grant from the Emory University Alzheimer's Disease Research Center (PHS AG025688) to D.W.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Neurosciences
  • Neurosciences & Neurology
  • NEUROSCIENCES
  • Alzheimer
  • locus ceruleus
  • memory
  • neurodegeneration
  • noradrenaline
  • PROTEIN-KINASE-II
  • ALZHEIMERS-DISEASE
  • LOCUS-COERULEUS
  • TRANSGENIC MICE
  • NUCLEUS BASALIS
  • NEURONAL LOSS
  • NOREPINEPHRINE
  • DEGENERATION
  • MECHANISMS
  • EXPRESSION

Ear2 Deletion Causes Early Memory and Learning Deficits in APP/PS1 Mice

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Journal Title:

Journal of Neuroscience

Volume:

Volume 34, Number 26

Publisher:

, Pages 8845-8854

Type of Work:

Article | Final Publisher PDF

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.

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© 2014 the authors.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License (http://creativecommons.org/licenses/by-nc-sa/3.0/).

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