Transgenic mice over-expressing mutant APP K670N,M671L and either mutant PS1M146V or PS1M146L transgenes were generated and examined by immunohistochemistry using antibodies directed against 15 different A( subtypes and glial fibrillary acidic protein (GFAP). A( deposition began in the cingulate cortex of double mutant heterozygous transgenic mice at approximately 10 weeks, in a pattern that correlated well with the expression pattern of the PS1 transgene. By six months of age, the mice had extensive amyloid deposition throughout the hippocampus and cortex and deposition had also spread to other regions of the brain. Immunohistochemistry identified deposits consisting of N-terminal normal and modified forms of A( reminiscent of those found in human AD brain and the deposits were highly congophilic. Both immunohistochemistry and mass spectrometry showed that A(42 forms were under-represented relative to A(40 forms and A(43 was undetectable in the transgenic mouse br ains. In P SAPP mice over 14 months of age, there was both compact and diffuse A( immunoreactivity throughout the cortex and hippocampus. Amyloid 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, whereas in the APP age-matched littermates, GFAP immunoreactive astrocytes still clustered tightly around the deposit. In conclusion, these mice develop robust AD type amyloid pathology at a young age that recapitulates the human phenotype and they develop a marked inflammatory response that changes with amyloid exposure time, or load.