Spatial and temporal control of age-related APP processing in genomic-based β-secretase transgenic mice

Genetic mutations associated with Alzheimer's disease (AD) in the Amyloid Precursor Protein (APP) gene specifically alter the production of the APP processing product, amyloid-beta (A beta) peptide, generated by beta- and gamma-secretases. The accumulation and deposition of A beta is hypothesized to cause AD pathogenesis, leading to the debilitating neurological deficits observed in AD patients. However, it is unclear how processing of APP to generate A beta corresponds with the age-dependent pattern of brain-regional neurodegeneration common in AD. We have previously shown that overexpression of BACE1, the primary beta-secretase gene, in mice expressing an AD mutant form of APP leads to significantly elevated regional A beta levels, which coincide with the regional pattern of A beta deposition. In the current study, we have used our genomic-based beta-secretase transgenic mice to determine how BACE1 regulates the spatial and temporal pattern of A beta production throughout post-natal development. Specifically, we observed unique differences in the brain-regional expression pattern between neonatal and adult BACE1 transgenic mice. These alterations in the BACE1 expression profile directly corresponds with age-related differences in regional A beta production and deposition. These studies indicate that modulation of BACE1 expression leads to dramatic alterations in APP processing and AD-like neuropathology. Furthermore, our studies provide further evidence that BACE1 plays a major role in the regulation of the APP processing pathway, influencing the age-dependent onset of AD pathogenesis. (c) 2005 Elsevier Inc. All rights reserved.