title: Repeated administration of the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) modulates neuroinflammation and amyloid plaque load in mice bearing amyloid precursor protein and presenilin-1 mutant transgenes.
abstract: BACKGROUND
  Data indicates anti-oxidant, anti-inflammatory and pro-cognitive properties of noradrenaline and analyses of post-mortem brain of Alzheimer's disease (AD) patients reveal major neuronal loss in the noradrenergic locus coeruleus (LC), the main source of CNS noradrenaline (NA). The LC has projections to brain regions vulnerable to amyloid deposition and lack of LC derived NA could play a role in the progression of neuroinflammation in AD. Previous studies reveal that intraperitoneal (IP) injection of the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) can modulate neuroinflammation in amyloid over-expressing mice and in one study, DSP-4 exacerbated existing neurodegeneration.
  
  
  METHODS
  TASTPM mice over-express human APP and beta amyloid protein and show age related cognitive decline and neuroinflammation. In the present studies, 5 month old C57/BL6 and TASTPM mice were injected once monthly for 6 months with a low dose of DSP-4 (5 mg kg-1) or vehicle. At 8 and 11 months of age, mice were tested for cognitive ability and brains were examined for amyloid load and neuroinflammation.
  
  
  RESULTS
  At 8 months of age there was no difference in LC tyrosine hydroxylase (TH) across all groups and cortical NA levels of TASTPM/DSP-4, WT/Vehicle and WT/DSP-4 were similar. NA levels were lowest in TASTPM/Vehicle. Messenger ribonucleic acid (mRNA) for various inflammatory markers were significantly increased in TASTPM/Vehicle compared with WT/Vehicle and by 8 months of age DSP-4 treatment modified this by reducing the levels of some of these markers in TASTPM. TASTPM/Vehicle showed increased astrocytosis and a significantly larger area of cortical amyloid plaque compared with TASTPM/DSP-4. However, by 11 months, NA levels were lowest in TASTPM/DSP-4 and there was a significant reduction in LC TH of TASTPM/DSP-4 only. Both TASTPM groups had comparable levels of amyloid, microglial activation and astrocytosis and mRNA for inflammatory markers was similar except for interleukin-1 beta which was increased by DSP-4. TASTPM mice were cognitively impaired at 8 and 11 months but DSP-4 did not modify this.
  
  
  CONCLUSIONS
  These data reveal that a low dose of DSP-4 can have varied effects on the modulation of amyloid plaque deposition and neuroinflammation in TASTPM mice dependent on the duration of dosing.
authors.affiliation: Neurology & Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline Research & Development Limited, New Frontiers Science Park, Harlow, Essex, UK. pippa.l.pugh@gsk.com <pippa.l.pugh@gsk.com>
authors.forename: Perdita L
authors.initials: PL
authors.lastname: Pugh
authors.forename: Martin P
authors.initials: MP
authors.lastname: Vidgeon-Hart
authors.forename: Tracey
authors.initials: T
authors.lastname: Ashmeade
authors.forename: Ainsley A
authors.initials: AA
authors.lastname: Culbert
authors.forename: Zoe
authors.initials: Z
authors.lastname: Seymour
authors.forename: Marion J
authors.initials: MJ
authors.lastname: Perren
authors.forename: Flora
authors.initials: F
authors.lastname: Joyce
authors.forename: Simon T
authors.initials: ST
authors.lastname: Bate
authors.forename: Anna
authors.initials: A
authors.lastname: Babin
authors.forename: David J
authors.initials: DJ
authors.lastname: Virley
authors.forename: Jill C
authors.initials: JC
authors.lastname: Richardson
authors.forename: Neil
authors.initials: N
authors.lastname: Upton
authors.forename: David
authors.initials: D
authors.lastname: Sunter
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001596:Benzylamines / Q000008:administration & dosage* / Q000633:toxicity; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004334:Drug Administration Schedule; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D058225:Plaque, Amyloid / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D053764:Presenilin-1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D019076:Transgenes / Q000187:drug effects*
chemical_list: D016564:Amyloid beta-Protein Precursor; D001596:Benzylamines; D053764:Presenilin-1; C012102:DSP 4; D009638:Norepinephrine