Beta-secretase transgenic mice: Effects of BACE1 and BACE2 on Alzheimer's disease pathogenesis

Numerous investigations have demonstrated that genetic factors play a major role in the etiology of Alzheimer's disease (AD). Identification of mutations in amyloid precursor protein gene (APP ) on chromosome 21 has implicated the role this gene plays in early-onset (<60 years) familial AD. With the identification of the amyloid-beta peptide (Abeta) as a characteristic feature of the senile plaques in the AD brain, understanding how this peptide is generated and how it contributes to the pathogenesis of the disease has become a primary focus of investigation. APP processing involves a cleavage pathway carried out by three proteins, alpha-, beta-, and gamma-secretases. The Abeta peptide is generated by the cleavage of APP by beta-secretase followed by gamma-secretase cleavage. Studies have shown that mutations in APP found in a Swedish pedigree with FAD leads to a significant increase in total Abeta production. Modulation of the APP processing enzymes can provide insight into the critical relationship between Abeta production and AD pathogenesis. Two genes thought to be responsible for beta-secretase cleavage of APP encode the transmembrane aspartyl proteases, beta-site APP cleaving enzyme-1 (BACE1) and beta-site APP cleaving enzyme-2 (BACE2). Extensive in vitro analyses have demonstrated that BACE1 and BACE2 selectively cleave APP at the beta-secretase site. Overexpression of BACE1 in human cells expressing wild type APP or mutant APP results in an increased production of Abeta peptides. The goal of the current project has been to elucidate the role BACE1 and BACE2 play in generating Abeta from APP in vivo. The overall objective has been to analyze how genomic overexpression of these genes with other AD mutations leads to alterations in APP processing and neuropathology observed in AD. While BACE2 transgenics do not exhibit altered Abeta levels, BACE1 transgenics dramatically alter the production and deposition pattern of Abeta. These studies demonstrate how beta-secretase influences APP processing, resulting in significant consequences on the development of AD pathogenesis. Further studies will provide insight into the regulation of beta-secretase as a primary factor in AD neuropathology.