The role of secreted APP in modulation of the Akt survival signaling pathway and neuroprotection

• Applicant: Professor Dr. Donat Kögel
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: from 2014 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 258499424

The physiological roles of the amyloid precursor protein and its various cleavage products are hitherto not fully understood, but accumulating evidence suggests that loss of APP function underlies reduced neuronal plasticity, diminished synaptic signaling and enhanced susceptibility of neurons to cellular stress during brain aging. Previous studies from our lab suggest that sAPPalpha which is generated via cleavage of APP by the activity of alpha-secretase along the secretory pathway exerts potent neuroprotective effects via modulation of gene expression as well as by antagonizing neurotoxic stress conditions, thereby inhibiting stress-triggered cell death. In our most recent unpublished work, we could also demonstrate that sAPPalpha is a key activator of the Akt survival signaling pathway and that APP, but not APLP1 and APLP2 specifically functions as a receptor/co-receptor for sAPPalpha-mediated neuroprotection. These exciting novel findings provide a solid basis for a detailed molecular analysis of sAPPalpha-mediated neuroprotection in the proposed project. In particular, we will focus on APP functional domains and putative co-receptors required for intracellular transduction of sAPPalpha-mediated survival signaling, and on the relevant sAPPalpha downstream targets mediating neuroprotection.

• DFG Programme: Research Grants