Amyloid Phenotype Characterization of Transgenic Mice Overexpressing both Mutant Amyloid Precursor Protein and Mutant Presenilin 1 Transgenes

Abstract

Doubly transgenic mice (PSAPP) overexpressing mutant APP and PS1 transgenes were examined using antibodies to Aβ subtypes and glial fibrillary acidic protein (GFAP). Visible Aβ deposition began primarily in the cingulate cortex of PSAPP mice at approximately 10 weeks of age. By 6 months, the mice had extensive amyloid deposition throughout the hippocampus and cortex as well as other regions of the brain. Highly congophilic deposits consisting of N-terminal normal and modified forms of Aβ were identified, reminiscent of those found in human AD brain. Both immunohistochemistry and mass spectrometry showed that Aβ42 forms were underrepresented relative to Aβ40, and Aβ43 was undetectable. Deposits were associated with prominent gliosis which increased with age, but in 14-month-old PSAPP mice, GFAP immunoreactivity in the vicinity of amyloid deposits was substantially reduced compared to APP littermates. These mice have considerable utility in the study of the amyloid phenotype of AD.