Amyloid-β (Aβ) the primary component of the senile plaques found in Alzheimer's disease (AD) is generated by the rate-limiting cleavage of amyloid precursor protein (APP) by β-secretase followed by γ-secretase cleavage. Identification of the primary β-secretase gene,BACE1, provides a unique opportunity to examine the role this unique aspartyl protease plays in altering Aβ metabolism and deposition that occurs in AD. The current experiments seek to examine how modulating β-secretase expression and activity alters APP processing and Aβ metabolismin vivo. Genomic-basedBACE1transgenic mice were generated that overexpress humanBACE1mRNA and protein. The highest expressingBACE1transgenic line was mated to transgenic mice containing human APP transgenes. Our biochemical and histochemical studies demonstrate that mice overexpressing bothBACE1andAPPshow specific alterations in APP processing and age-dependent Aβ deposition. We observed elevated levels of Aβ isoforms as well as significant increases of Aβ deposits in these double transgenic animals. In particular, the double transgenics exhibited a unique cortical deposition profile, which is consistent with a significant increase of BACE1 expression in the cortex relative to other brain regions. Elevated BACE1 expression coupled with increased deposition provides functional evidence for β-secretase as a primary effector in regional amyloid deposition in the AD brain. Our studies demonstrate, for the first time, that modulation ofBACE1activity may play a significant role in AD pathogenesisin vivo.
Spatial and temporal control of age-related APP processing in genomic-based β-secretase transgenic mice
