title: PS2APP transgenic mice, coexpressing hPS2mut and hAPPswe, show age-related cognitive deficits associated with discrete brain amyloid deposition and inflammation.
abstract: Transgenic mice, expressing mutant beta-amyloid precursor proteins (betaAPPs), have lead to a better understanding of the pathophysiological processes in Alzheimer's disease (AD). In many of these models, however, the temporal development of cognitive decline and the relationship to Abeta deposition and inflammation are unclear. We now report a novel transgenic mouse line, PS2APP (PS2N141I x APPswe), which develops a severe cerebral amyloidosis in discrete brain regions, and present a cross-sectional analysis of these mice at 4, 8, 12, and 16 months of age. Each age cohort was investigated for changes in behavior, electrophysiology of synapse efficacy, ELISA-determined Abeta load, histopathology, and in immunoelectron microscopy. Cognitive deficits were first observed at 8 months when Abeta deposits and inflammation were restricted to discrete brain regions, namely the subiculum and frontolateral (motor and orbital) cortex. As early as 5 months, electron microscopy revealed the presence, in these regions, of pre-plaque, immunogold-labeled extracellular fibrillar Abeta. At the same age, increased levels of insoluble Abeta were detected by ELISA, with Abeta1-40 levels exceeding those of Abeta1-42. Further cognitive decline occurred in an age-related manner, and this was accompanied by the spread of amyloidosis to ultimately affect not only neo- and limbic cortices, but also thalamic and pontine nuclei. Dentate gyrus post-tetanic potentiation was significantly attenuated at 17 months, and there were also significant differences in paired-pulse parameters. This systematic cross-sectional study of the behavioral and pathological changes in the PS2APP mouse indicates that it develops age-related cognitive decline associated with severe amyloidosis and inflammation in discrete brain regions and therefore is suitable for testing a range of potential symptomatic and disease-modifying therapies for AD.
authors.affiliation: Department of Pharma Research Biology Discovery and Roche Center for Medical Genomics, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland. richards@balcab.ch
authors.forename: J Grayson
authors.initials: JG
authors.lastname: Richards
authors.forename: Guy A
authors.initials: GA
authors.lastname: Higgins
authors.forename: Abdel-Mouttalib
authors.initials: AM
authors.lastname: Ouagazzal
authors.forename: Laurence
authors.initials: L
authors.lastname: Ozmen
authors.forename: James N C
authors.initials: JN
authors.lastname: Kew
authors.forename: Bernd
authors.initials: B
authors.lastname: Bohrmann
authors.forename: Pari
authors.initials: P
authors.lastname: Malherbe
authors.forename: Manfred
authors.initials: M
authors.lastname: Brockhaus
authors.forename: Hansruedi
authors.initials: H
authors.lastname: Loetscher
authors.forename: Christian
authors.initials: C
authors.lastname: Czech
authors.forename: Gerda
authors.initials: G
authors.lastname: Huber
authors.forename: Horst
authors.initials: H
authors.lastname: Bluethmann
authors.forename: Helmut
authors.initials: H
authors.lastname: Jacobsen
authors.forename: John A
authors.initials: JA
authors.lastname: Kemp
mesh_terms: D000367:Age Factors; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000096:biosynthesis; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis* / Q000235:genetics; D000686:Amyloidosis / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D001923:Brain Chemistry; D003072:Cognition Disorders / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D003430:Cross-Sectional Studies; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D018450:Disease Progression; D006624:Hippocampus / Q000503:physiopathology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D018782:Maze Learning; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D016253:Microscopy, Immunoelectron; D009154:Mutation; D009473:Neuronal Plasticity / Q000235:genetics; D053766:Presenilin-2; D009435:Synaptic Transmission / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C508861:PSEN2 protein, human; D053766:Presenilin-2