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Author Notes:

Address correspondence to Michael T. Heneka, M.D., University of Bonn, Department of Neurology, Clinical Neuroscience, Sigmund-FreudStrasse 25, Bonn 53127, Germany; E-mail: michael.heneka@ukb.unibonn.de.

We thank Dainippon Sumitomo Pharmaceutical Company for their generous gift of L-threo-dihydroxyphenylserine. We also thank C. Jerome for technical assistance with mouse breeding and genotyping. We are grateful to C. Hülsmann for excellent technical assistance.

The authors report no biomedical financial interests or potential conflicts of interest.

Subjects:

Research Funding:

This work was supported by grants from the Interdisciplinary Center for Clinical Research (HEN3/003/06) to MTH and H-CP, the Institute for the Study of Aging to DW, and two grants from the Emory University Alzheimer's Disease Research Center (PHS AG025688) to DW.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Neurosciences
  • Psychiatry
  • Neurosciences & Neurology
  • NEUROSCIENCES
  • PSYCHIATRY, SCI
  • Alzheimer's disease
  • CaMKII
  • degeneration
  • locus coeruleus
  • memory
  • noradrenaline
  • norepinephrine
  • pathogenesis
  • DOPAMINE-BETA-HYDROXYLASE
  • LOCUS-CERULEUS DEGENERATION
  • LONG-TERM POTENTIATION
  • PROTEIN-KINASE-II
  • ADULT-RAT BRAIN
  • ALZHEIMERS-DISEASE
  • TRANSGENIC MICE
  • NEUROTROPHIC FACTOR
  • SOLUBLE OLIGOMERS
  • NEURONAL LOSS

Selective Loss of Noradrenaline Exacerbates Early Cognitive Dysfunction and Synaptic Deficits in APP/PS1 Mice

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Journal Title:

Biological Psychiatry

Volume:

Volume 73, Number 5

Publisher:

, Pages 454-463

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Background: Degeneration of the locus coeruleus (LC), the major noradrenergic nucleus in the brain, occurs early and is ubiquitous in Alzheimer's disease (AD). Experimental lesions to the LC exacerbate AD-like neuropathology and cognitive deficits in several transgenic mouse models of AD. Because the LC contains multiple neuromodulators known to affect amyloid β toxicity and cognitive function, the specific role of noradrenaline (NA) in AD is not well understood. Methods: To determine the consequences of selective NA deficiency in an AD mouse model, we crossed dopamine β-hydroxylase (DBH) knockout mice with amyloid precursor protein (APP)/presenilin-1 (PS1) mice overexpressing mutant APP and PS1. Dopamine β-hydroxylase (-/-) mice are unable to synthesize NA but otherwise have normal LC neurons and co-transmitters. Spatial memory, hippocampal long-term potentiation, and synaptic protein levels were assessed. Results: The modest impairments in spatial memory and hippocampal long-term potentiation displayed by young APP/PS1 or DBH (-/-) single mutant mice were augmented in DBH (-/-)/APP/PS1 double mutant mice. Deficits were associated with reduced levels of total calcium/calmodulin-dependent protein kinase II and N-methyl-D-aspartate receptor 2A and increased N-methyl-D-aspartate receptor 2B levels and were independent of amyloid β accumulation. Spatial memory performance was partly improved by treatment with the NA precursor drug L-threo-dihydroxyphenylserine. Conclusions: These results indicate that early LC degeneration and subsequent NA deficiency in AD may contribute to cognitive deficits via altered levels of calcium/calmodulin-dependent protein kinase II and N-methyl-D-aspartate receptors and suggest that NA supplementation could be beneficial in early AD.

Copyright information:

© 2013 Society of Biological Psychiatry.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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