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  Selective loss of noradrenaline exacerbates early cognitive dysfunction and synaptic deficits in APP/PS1 mice.

Hammerschmidt, T., Kummer, M. P., Terwel, D., Martinez, A., Gorji, A., Pape, H. C., et al. (2013). Selective loss of noradrenaline exacerbates early cognitive dysfunction and synaptic deficits in APP/PS1 mice. Biological Psychiatry, 73(5), 454-463. doi:10.1016/j.biopsych.2012.06.013.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-000E-F5F9-8 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0027-C835-1
Genre: Journal Article

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 Creators:
Hammerschmidt, T., Author
Kummer, M. P., Author
Terwel, D., Author
Martinez, A.1, Author              
Gorji, A., Author
Pape, H. C., Author
Rommelfanger, K. S., Author
Schroeder, J. P., Author
Stoll, M., Author
Schultze, J., Author
Weinshenker, D., Author
Heneka, M. T., Author
Affiliations:
1Department of Genes and Behavior, MPI for biophysical chemistry, Max Planck Society, ou_persistent34              

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Free keywords: Alzheimer’s disease, CaMKII, degeneration, locus coeruleus, memory, noradrenaline, norepinephrine, pathogenesis
 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 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 -hydroxylase (DBH) knockout mice with amyloid precursor protein (APP)/presenilin-1 (PS1) mice overexpressing mutant APP and PS1. Dopamine -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 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 subsequentNAdeficiency inADmay 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.

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Language(s): eng - English
 Dates: 2013-03-01
 Publication Status: Published in print
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 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1016/j.biopsych.2012.06.013
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Title: Biological Psychiatry
Source Genre: Journal
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Pages: - Volume / Issue: 73 (5) Sequence Number: - Start / End Page: 454 - 463 Identifier: -