BACE1 overexpression regulates amyloid precursor protein cleavage and interaction with the ShcA adapter.

The amyloid precursor protein (APP) is a cell surface protein with a large extracellular N-terminal domain, a single transmembrane segment, and a short cytoplasmic tail. Its location and structural features are characteristic of a receptor for signal transduction. Yet, the physiological function of APP is unclear, although it is well documented that APP's proteolytic processing, through the formation of membrane-bound C-terminal fragments (CTFs) and of beta-amyloid peptides, likely influences the development of Alzheimer's disease (AD). There is evidence that BACE1 is the enzyme responsible for beta-site cleavage of the APP and for the generation of CTFs. BACE1 expression is upregulated in AD brain, and we have recently shown in human brain and in vitro that BACE product CTFs, when phosphorylated in tyrosine residues, interact with the adaptor proteins ShcA and Grb2, which usually are involved in signal transduction pathways. We investigated the interaction between ShcA, APP, and CTFs in the H4 human cell line that overexpresses BACE1 to clarify the significance of such interactions in vitro and for AD generation. Our result show that the APP, CTF, and ShcA interaction is induced only upon overexpression of BACE1 either transiently or in stable cell lines. In particular, although BACE1 drives the formation of C99 and C89 CTFs, only C99 interacts with the ShcA adaptor protein. Therefore, our data suggest that BACE1 activity influences APP processing and its intracellular signaling through the ShcA adaptor protein.