Abeta42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology

EMBO Rep. 2006 Sep;7(9):940-6. doi: 10.1038/sj.embor.7400784. Epub 2006 Aug 11.

Abstract

We have generated a novel transgenic mouse model on a C57BL/6J genetic background that coexpresses KM670/671NL mutated amyloid precursor protein and L166P mutated presenilin 1 under the control of a neuron-specific Thy1 promoter element (APPPS1 mice). Cerebral amyloidosis starts at 6-8 weeks and the ratio of human amyloid (A)beta42 to Abeta40 is 1.5 and 5 in pre-depositing and amyloid-depositing mice, respectively. Consistent with this ratio, extensive congophilic parenchymal amyloid but minimal amyloid angiopathy is observed. Amyloid-associated pathologies include dystrophic synaptic boutons, hyperphosphorylated tau-positive neuritic structures and robust gliosis, with neocortical microglia number increasing threefold from 1 to 8 months of age. Global neocortical neuron loss is not apparent up to 8 months of age, but local neuron loss in the dentate gyrus is observed. Because of the early onset of amyloid lesions, the defined genetic background of the model and the facile breeding characteristics, APPPS1 mice are well suited for studying therapeutic strategies and the pathomechanism of amyloidosis by cross-breeding to other genetically engineered mouse models.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Protein Precursor / genetics*
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Cerebral Amyloid Angiopathy / genetics
  • Cognition
  • Disease Models, Animal*
  • Inflammation / pathology
  • Male
  • Membrane Proteins / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neocortex / metabolism*
  • Neurons / pathology
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism*
  • Presenilin-1

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Membrane Proteins
  • PSEN1 protein, human
  • Peptide Fragments
  • Presenilin-1
  • amyloid beta-protein (1-42)