Physiological relevance and dynamic regulation of APLP-mediated cell:cell interactions

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The amyloid precursor protein (APP) and the homologous amyloid precursor-like proteins (APLPs) are members of an evolutionary conserved protein family. The current knowledge suggests key physiological functions for APLPs among family members. Recently, we have shown that APLP1 mainly localizes to the cell surface in contrast to APP and APLP2. Our newly discovered Zn-dependent generation of APLP1 mediated cell:cell contacts opens up new perspectives for the functional characterization of APP family proteins. Thus, the main goal of this project is to investigate the biochemical basis, the dynamics and the cell-biological relevance of APP and AP-like proteins (APLP1, APLP2) in forming cis-bridged homo- or heterooligomeric complexes and trans-interacting cell:cell contacts. Furthermore, we will investigate how α- or β-secretase cleavages affect cell:cell contacts mediated by cis- or cis/trans-interacting complexes. One challenge of the proposed project is the analysis of APP:APLP1 complex processing of covalently linked heterodimers of Aß and Aß-like peptides. This is expected to lead to the identification of the exact cleavage sites of Aß-like peptides derived from APLP1 and contribute to understand the functional role of APLPs in the AD pathogenesis.