title: Selective loss of noradrenaline exacerbates early cognitive dysfunction and synaptic deficits in APP/PS1 mice.
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.
authors.affiliation: Department of Neurology, Clinical Neurosciences, University of Bonn, Bonn, Germany.
authors.forename: Thea
authors.initials: T
authors.lastname: Hammerschmidt
authors.forename: Markus P
authors.initials: MP
authors.lastname: Kummer
authors.forename: Dick
authors.initials: D
authors.lastname: Terwel
authors.forename: Ana
authors.initials: A
authors.lastname: Martinez
authors.forename: Ali
authors.initials: A
authors.lastname: Gorji
authors.forename: Hans-Christian
authors.initials: HC
authors.lastname: Pape
authors.forename: Karen S
authors.initials: KS
authors.lastname: Rommelfanger
authors.forename: Jason P
authors.initials: JP
authors.lastname: Schroeder
authors.forename: Monika
authors.initials: M
authors.lastname: Stoll
authors.forename: Joachim
authors.initials: J
authors.lastname: Schultze
authors.forename: David
authors.initials: D
authors.lastname: Weinshenker
authors.forename: Michael T
authors.initials: MT
authors.lastname: Heneka
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D003071:Cognition / Q000502:physiology*; D004299:Dopamine beta-Hydroxylase / Q000235:genetics / Q000378:metabolism*; D005106:Exploratory Behavior / Q000502:physiology; D017774:Long-Term Potentiation / Q000502:physiology*; D018782:Maze Learning / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000235:genetics / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1; D014446:Tyrosine 3-Monooxygenase; D004299:Dopamine beta-Hydroxylase; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D009638:Norepinephrine