br Secretase in inflammatory diseases Secretase appears

γ-Secretase in inflammatory diseases γ-Secretase appears to play a more important role than previously recognized in inflammatory diseases. Studies have shown that mice partially deficient in PS genes (PS1+/− PS2−/−) develop an immune system deficit in late adulthood, such as ulcerated skin or a swollen neck (Tournoy et al., 2004). In addition, inflammatory reactions, such as an enlarged spleen, leukocytosis, and γ-globulinemia, have been observed in these mice. Further, the partial PS knockout causes a severe autoimmune phenotype with nuclear autoantibodies similar to human systemic lupus erythematosis (SLE) (Tournoy et al., 2004), consistent with γ-secretase (or PS) regulating some important functions of the immune system. Inhibition of Notch signaling using γ-secretase inhibitors reduces the production of abnormal double-negative T GSK343 receptor (DNTs) that are seen in autoimmune lymphoproliferative syndrome (ALPS) and SLE mouse models, and treatment with γ-secretase inhibitors reduces lymphoproliferation (i.e. by decreased lymph node and spleen sizes), cytokine production, and dsDNA autoantibody production (Teachey et al., 2008). These findings are consistent with the possibility that γ-secretase may regulate the immune response through Notch signaling. The role of Notch signaling through γ-secretase also appears to be prominent in several recent studies of experimental inflammatory conditions listed below.
γ-Secretase-mediated inflammatory mechanisms
γ-Secretase inhibitors to target inflammation
Conclusions and future research To date, more than 90 type I membrane proteins and receptors have been identified as γ-secretase substrates (Haapasalo & Kovacs, 2011). Many of these substrates function as signaling molecules and control a variety of cellular processes that include axon guidance, neurite outgrowth, cell adhesion, cell migration, cell fate determination or formation and maintenance of synapses (Jurisch-Yaksi et al., 2013). However, only a few such substrates and γ-cleavage products have been studied in the context of pathogenesis of inflammatory diseases (Table 1). Therefore, identification of the substrate and full understanding of the pathophysiological consequences of its processing by γ-secretase within a specific inflammatory disease state is necessary to comprehend the key molecular mechanisms and to then develop effective therapeutic strategies. γ-Secretase is a complex and fascinating enzyme with numerous substrates, with many recent studies having revealed an important regulatory role in inflammatory responses involving various cell types. For example, the PS mutation can exacerbate inflammation in AD, resulting in the early onset of familial AD. Such studies have provided initial support for PS/γ-secretase as a therapeutic target in inflammatory diseases. In fact, targeting the Notch signaling pathway by γ-secretase inhibitors has been suggested as a therapeutic approach for certain types of inflammatory diseases. However, chronic treatment using certain pharmacological inhibitors of γ-secretase have been found to have detrimental side effects in patients (Rocher-Ros et al., 2010), and therefore the development of γ-secretase modulators with enhanced specificity for the enzymatic/cellular target is likely to be a much more useful approach than the complete inhibition of γ-secretase.
Conflicts of interest
Introduction γ-secretase (GS) is an intramembrane-cleaving aspartyl protease involved in the last processing step of amyloid precursor protein (APP) to produce different amyloid-β (Aβ) isoforms [1]. Normal processing of 99-residue C-terminal fragment of APP (C99) by GS leads to the production of the 40-amino acid length isoform (Aβ40). Aberrant C99 cleavage results in an increased production of the longer and toxic 42-amino acid species of Aβ (Aβ42) over the less toxic Aβ40 [2] that leads to their oligomerization and aggregation in the brain and that have been associated with the development and progression of Alzheimer's disease [3,4].