P4-194: Presenilin-dependent gamma-secretase proteolysis of cytokine receptors

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Following the identification of presenilins and their genetic association with the onset of Familial Alzheimer's disease, independent studies have shown that presenilins are the catalytic component of the gamma-secretase complex associated with the proteolytic cleavage of Amyloid Precursor Protein (APP), generation of amyloid-beta peptides and onset of Alzheimer's disease. Recently, many groups have revealed several additional presenilin-interacting proteins and gamma-secretase cleavage substrates, suggesting a diversity of roles for presenilin during development and adult life, some of which might contribute to Alzheimer's disease progression. Cell culture, Western blot, co-immunoprecipitation, molecular cloning. In our studies we have demonstrated that several members of the tumour necrosis factor (TNF)/nerve growth factor (NGF) and interleukin-1 (IL-1)/toll-like receptor (TLR) super families can be proteolytically processed in a manner similar to APP. We show that select members of the TNF/NGF and IL-1/TLR super families undergo ligand-dependant intramembrane proteolytic processing, mediated by presenilin-dependent γ-secretase activity. A metalloprotease-dependent proteolytic event liberates soluble receptor-ectodomains and produces membrane-associated C-terminal fragments (CTF). These membrane-anchored CTFs are substrates for subsequent γ-secretase cleavage, which generates TNF/NGF and IL-1/TLR derived intracellular domains (ICD). Generation of the ICD's is independently inhibited by specific pharmacological γ-secretase inhibitors, expression of dominant negative presenilin-1 or presenilin deficiency. Attenuation of γ-secretase activity or presenilin deficiency also impairs responsiveness to TNF/NGF and IL-1/TLR ligand-stimulated activation of the mitogen activated protein kinases (MAPK), nuclear factor κB (NF–κB) and cytokine secretion. Our data suggests that increased proteolytic processing and secretion of these cytokine and growth factor receptors may, through signalling deficits in the associated pathways, mediate nervous system inflammation in patients with Alzheimer's disease.