Beta-Secretase Trangenic Mice

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-β peptide (Aβ) 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, α-, β-, and γ-secretases. The Aβ peptide is generated by the cleavage of APP by β-secretase followed by γ-secretase cleavage. Studies have shown that mutations in APP found in a Swedish pedigree with FAD leads to a significant increase in total Aβ production. Modulation of the APP processing enzymes can provide insight into the critical relationship between Aβ production and AD pathogenesis. Two genes thought to be responsible for β-secretase cleavage of APP encode the transmembrane aspartyl proteases, β-site APP cleaving enzyme-1 (BACE1) and β-site APP cleaving enzyme-2 (BACE2). Extensive in vitro analyses have demonstrated that BACE1 and BACE2 selectively cleave APP at the β-secretase site. Overexpression of BACE1 in human cells expressing wild type APP or mutant APP results in an increased production of Aβ peptides. The goal of the current project has been to elucidate the role BACE1 and BACE2 play in generating Aβ 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 BACE2transgenics do not exhibit altered Aβ levels, BACE1 transgenics dramatically alter the production and deposition pattern of Aβ. These studies demonstrate how β-secretase influences APP processing, resulting in significant consequences on the development of AD pathogenesis. Further studies will provide insight into the regulation of β-secretase as a primary factor in AD neuropathology.