Identification and characterization of modulators affecting Amyloid precursor protein (APP) family members synaptogenic activity

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Besides its fundamental role in Alzheimer Disease pathology, the Amyloid precursor protein (APP) has important physiological functions at the synapse. Interestingly, actual data suggest that APP and its homologues APLP1 and APLP2 act together in different synaptic processes and in doing so secreted (sAPP) and full-length APP fulfill different functions. So deficits in synapse formation and LTP observed in APP/APL2 knockout mice can only partly be rescued by sAPP. We and others have shown that full-length APP, APLP1 and APLP2 can dimerize in trans-orientation and could show that expression of APP in HEK293 cells co-cultured with primary neurons potently promotes synaptogenesis in contacting axons, similar to other synaptic adhesion molecules, such as Neuroligins/Neurexins. In a pre-screen based on in vitro trans-dimerization of purified APP/APLPs we observed that different cell types, including neurons and glia cells secrete diverse protein components modulating APP trans-directed dimerization. In first biochemical analysis we could identify one of those modulators affecting trans-directed interaction of APP and APLP1. In context of this application we intend to screen for additional modulators of APP/APLPs trans-interaction and like to analyze their function in APP/APLPs synapse formation. For this purpose we intend to analyze the impact of those modulators on APP/APLPs-mediated synapse formation in primary neurons, on hemi-synapses in the mixed co-culture assay and on synapse dynamics by long-term in vivo two-photon live cell imaging. In this context we will also use neuronal cultures from different single or double knockouts of APP, APLP1 and APLP2. Together these studies will help to increase our understanding of APP/APLPs physiological function in interplay with other synaptic proteins in synapse modulation.