title: Early-onset and robust amyloid pathology in a new homozygous mouse model of Alzheimer's disease.
abstract: BACKGROUND
  Transgenic mice expressing mutated amyloid precursor protein (APP) and presenilin (PS)-1 or -2 have been successfully used to model cerebral beta-amyloidosis, one of the characteristic hallmarks of Alzheimer's disease (AD) pathology. However, the use of many transgenic lines is limited by premature death, low breeding efficiencies and late onset and high inter-animal variability of the pathology, creating a need for improved animal models. Here we describe the detailed characterization of a new homozygous double-transgenic mouse line that addresses most of these issues.
  
  
  RESULTS
  The transgenic mouse line (ARTE10) was generated by co-integration of two transgenes carrying the K670N/M671L mutated amyloid precursor protein (APP(swe)) and the M146V mutated presenilin 1 (PS1) both under control of a neuron-specific promoter. Mice, hemi- as well as homozygous for both transgenes, are viable and fertile with good breeding capabilities and a low rate of premature death. They develop robust AD-like cerebral beta-amyloid plaque pathology with glial inflammation, signs of neuritic dystrophy and cerebral amyloid angiopathy. Using our novel image analysis algorithm for semi-automatic quantification of plaque burden, we demonstrate an early onset and progressive plaque deposition starting at 3 months of age in homozygous mice with low inter-animal variability and 100%-penetrance of the phenotype. The plaques are readily detected in vivo by PiB, the standard human PET tracer for AD. In addition, ARTE10 mice display early loss of synaptic markers and age-related cognitive deficits. By applying a gamma-secretase inhibitor we show a dose dependent reduction of soluble amyloid beta levels in the brain.
  
  
  CONCLUSIONS
  ARTE10 mice develop a cerebral beta-amyloidosis closely resembling the beta-amyloid-related aspects of human AD neuropathology. Unifying several advantages of previous transgenic models, this line particularly qualifies for the use in target validation and for evaluating potential diagnostic or therapeutic agents targeting the amyloid pathology of AD.
authors: Evotec Neurosciences GmbH, Hamburg, Germany. antje.willuweit@evotec.com
authors: Antje
authors: A
authors: Willuweit
authors: Joachim
authors: J
authors: Velden
authors: Robert
authors: R
authors: Godemann
authors: Andre
authors: A
authors: Manook
authors: Fritz
authors: F
authors: Jetzek
authors: Hartmut
authors: H
authors: Tintrup
authors: Gunther
authors: G
authors: Kauselmann
authors: Branko
authors: B
authors: Zevnik
authors: Gjermund
authors: G
authors: Henriksen
authors: Alexander
authors: A
authors: Drzezga
authors: Johannes
authors: J
authors: Pohlner
authors: Michael
authors: M
authors: Schoor
authors: John A
authors: JA
authors: Kemp
authors: Heinz
authors: H
authors: von der Kammer
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000686:Amyloidosis / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006720:Homozygote; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics; D011401:Promoter Regions, Genetic
chemical_list: D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1