title: Effects of sub-chronic donepezil on brain Abeta and cognition in a mouse model of Alzheimer's disease.
abstract: BACKGROUND
  Acetylcholinesterase inhibitors (AChEIs) are approved to treat the symptoms of mild to moderate Alzheimer's disease by restoring acetylcholine levels at synapses where the neurotransmitter has been depleted due to neurodegeneration. This assumption is challenged by more recent clinical studies suggesting the potential for disease-modifying effects of AChEIs as well as in vitro studies showing neuroprotective effects. However, few preclinical studies have assessed whether the improvement of cognitive symptoms may be mediated by reductions in Abeta or Tau pathology.
  
  
  OBJECTIVE
  The objective of the present study was to determine whether short-duration treatment with donepezil could improve spatial learning and memory in transgenic mice overexpressing mutant human amyloid precursor protein (hAPP) and presenilin 1 (PS1) (Dewachter et al., J Neurosci 20(17):6452-6458, 2000) after amyloid pathology has fully developed, consistent with early stages of Alzheimer'sdisease in humans. In parallel, the effect of donepezil treatment on brain amyloid, Tau, and glial endpoints was measured.
  
  
  RESULTS
  This study showed a significant improvement in reference memory in hAPP/PS1 mice along with dose-dependent reductions in brain amyloid-β (Aβ).
  
  
  CONCLUSIONS
  These results suggest that the observed cognitive improvement produced by donepezil in Alzheimer's disease may be due, at least in part, to reduction of brain Aβ.
authors.affiliation: Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT, 06492, USA, amy.easton@bms.com.
authors.forename: Amy
authors.initials: A
authors.lastname: Easton
authors.forename: Sethu
authors.initials: S
authors.lastname: Sankaranarayanan
authors.forename: An
authors.initials: A
authors.lastname: Tanghe
authors.forename: Dick
authors.initials: D
authors.lastname: Terwel
authors.forename: Alan X
authors.initials: AX
authors.lastname: Lin
authors.forename: Nina
authors.initials: N
authors.lastname: Hoque
authors.forename: Clotilde
authors.initials: C
authors.lastname: Bourin
authors.forename: Huidong
authors.initials: H
authors.lastname: Gu
authors.forename: Michael
authors.initials: M
authors.lastname: Ahlijanian
authors.forename: Linda
authors.initials: L
authors.lastname: Bristow
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology; D004195:Disease Models, Animal; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007189:Indans / Q000008:administration & dosage / Q000494:pharmacology*; D008568:Memory / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D053764:Presenilin-1 / Q000235:genetics; D013569:Synapses
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D053764:Presenilin-1; D000077265:Donepezil