PS2APP transgenic mice, coexpressing hPS2mut and hAPPswe, show age-related cognitive deficits associated with discrete brain amyloid deposition and inflammation - Archive ouverte HAL Access content directly
Journal Articles Journal of Neuroscience Year : 2003

PS2APP transgenic mice, coexpressing hPS2mut and hAPPswe, show age-related cognitive deficits associated with discrete brain amyloid deposition and inflammation

J. Grayson Richards
  • Function : Author
Guy A. Higgins
  • Function : Author
Laurence Ozmen
  • Function : Author
James N. C. Kew
  • Function : Author
Bernd Bohrmann
  • Function : Author
Pari Malherbe
  • Function : Author
Manfred Brockhaus
  • Function : Author
Hansruedi Loetscher
  • Function : Author
Christian Czech
  • Function : Author
Gerda Huber
  • Function : Author
Horst Bluethmann
  • Function : Author
Helmut Jacobsen
  • Function : Author
John A. Kemp
  • Function : Author

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.

Dates and versions

hal-04156291 , version 1 (07-07-2023)

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J. Grayson Richards, Guy A. Higgins, Abdel Mouttalib Ouagazzal, Laurence Ozmen, James N. C. Kew, et al.. PS2APP transgenic mice, coexpressing hPS2mut and hAPPswe, show age-related cognitive deficits associated with discrete brain amyloid deposition and inflammation. Journal of Neuroscience, 2003, 23 (26), pp.8989-9003. ⟨10.1523/JNEUROSCI.23-26-08989.2003⟩. ⟨hal-04156291⟩
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