y-Secretase-dependent processes in microglial functions

• Applicant: Professor Dr. Jochen Walter, Ph.D.
• Subject Area: Clinical Neurology; Neurosurgery and Neuroradiology
• Term: from 2007 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 33995431

Presenilin (PS) proteins are catalytically active components of y-secretase complexes that cleave the ß-amyloid precursor protein (ßAPP) in the generation of the Alzheimer disease (AD)-associated amyloid ß-peptide (Aß). Interestingly, mutations in the two presenilin (PS) genes are a major cause of early onset familial AD. In addition to ßAPP, y-secretase cleaves many additional type I membrane proteins. Consistent with cleavage of multiple protein substrates, y-secretase is implicated in different trafficking and intracellular signaling pathways thereby regulating cellular metabolism and differentiation. In the last funding period, we established a functional role of PS/y-secretase in microglia. Importantly, pathogenic mutations of PSI decreased the migration and phagocytic activity of microglia. We also identified TREM2 as a microglia-specific y-secretase substrate. We now aim to identify molecular mechanisms underlying the y-secretase dependent migration and phagocytosis in microglia, and characterize the functional implications of TREM2 processing in cell culture and in vivo models. Together, the proposed project should give insight into physiological and pathophysiological functions of y-secretase in microglia.

• DFG Programme: Clinical Research Units
• Subproject of: KFO 177: Innate Immunity in Chronic Neurodegeneration