[en] 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.
Disciplines :
Neurology
Author, co-author :
Hammerschmidt, Thea; Department of Neurology, Clinical Neurosciences, University of Bonn, Bonn, Germany
Kummer, Markus P; Department of Neurology, University of Bonn, Deutsches Zentrum für Neurodegenerative Erkrankungen, Bonn 53127, Germany
Terwel, Dick; Department of Neurology, University of Bonn, Deutsches Zentrum für Neurodegenerative Erkrankungen, Bonn 53127, Germany
Martinez, Ana; Genes and Behavior Department, Max Planck Institute of Biophysical Chemistry, Göttingen, Germany
Gorji, Ali; Institute of Physiology i, Westfälische Wilhelms-University Münster, Münster, Germany
Pape, Hans-Christian; Institute of Physiology i, Westfälische Wilhelms-University Münster, Münster, Germany
Rommelfanger, Karen S; Department of Human Genetics, Emory University, Atlanta, GA, United States
Schroeder, Jason P; Department of Human Genetics, Emory University, Atlanta, GA, United States
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.
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