title: Abeta42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology.
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.
authors.affiliation: Department of Cellular Neurology, Hertie-Institute for Clinical Brain Research, Otfried-Müller Strasse 27, D-72076 Tübingen, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Radde
authors.forename: Tristan
authors.initials: T
authors.lastname: Bolmont
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Kaeser
authors.forename: Janaky
authors.initials: J
authors.lastname: Coomaraswamy
authors.forename: Dennis
authors.initials: D
authors.lastname: Lindau
authors.forename: Lars
authors.initials: L
authors.lastname: Stoltze
authors.forename: Michael E
authors.initials: ME
authors.lastname: Calhoun
authors.forename: Fabienne
authors.initials: F
authors.lastname: Jäggi
authors.forename: Hartwig
authors.initials: H
authors.lastname: Wolburg
authors.forename: Simon
authors.initials: S
authors.lastname: Gengler
authors.forename: Christian
authors.initials: C
authors.lastname: Haass
authors.forename: Bernardino
authors.initials: B
authors.lastname: Ghetti
authors.forename: Christian
authors.initials: C
authors.lastname: Czech
authors.forename: Christian
authors.initials: C
authors.lastname: Hölscher
authors.forename: Paul M
authors.initials: PM
authors.lastname: Mathews
authors.forename: Mathias
authors.initials: M
authors.lastname: Jucker
mesh_terms: D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D016657:Cerebral Amyloid Angiopathy / Q000235:genetics; D003071:Cognition; D004195:Disease Models, Animal; D007249:Inflammation / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019579:Neocortex / Q000378:metabolism*; D009474:Neurons / Q000473:pathology; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D053764:Presenilin-1
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C075222:amyloid beta-protein (1-42)