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The Journal of Neuroscience, October 1, 2003, 23(26):8989-9003

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Behavioral/Systems/Cognitive
PS2APP Transgenic Mice, Coexpressing hPS2mut and hAPPswe, Show Age-Related Cognitive Deficits Associated with Discrete Brain Amyloid Deposition and Inflammation

J. Grayson Richards,^1 * Guy A. Higgins,^1 * Abdel-Mouttalib Ouagazzal,¹ Laurence Ozmen,¹ James N. C. Kew,¹ Bernd Bohrmann,¹ Pari Malherbe,¹ Manfred Brockhaus,¹ Hansruedi Loetscher,¹ Christian Czech,¹ Gerda Huber,¹ Horst Bluethmann,² Helmut Jacobsen,¹ and John A. Kemp¹

¹Department of Pharma Research Biology Discovery and ²Roche Center for Medical Genomics, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland

Transgenic mice, expressing mutant -amyloid precursor proteins (APPs), 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 A deposition and inflammation are unclear. We now report a novel transgenic mouse line, PS2APP (PS2_N141I x APP_swe), 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 A load, histopathology, and in immunoelectron microscopy. Cognitive deficits were first observed at 8 months when A 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 A. At the same age, increased levels of insoluble A were detected by ELISA, with A_1-40 levels exceeding those of A_1-42. 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.

Key words: Alzheimer; PS2APP; transgenic; amyloid -protein; amyloid precursor protein; presenilin 2; plaque; inflammation; LTP; cognition

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Received Feb 21, 2003; revised August 14, 2003; accepted August 15, 2003.

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