Presenilin-dependent gamma-secretase activity modulates thymocyte development

In neuronal cells, presenilin-dependent gamma -secretase activity cleaves a myloid precursor proteins to release A beta peptides, and also catalyzes th e release of the intracellular domain of the transmembrane receptor Notch. Accumulation of aberrant A beta peptides appears to be causally related to Alzheimer`s disease. Inhibition of A beta peptide production is therefore a potential target for therapeutic intervention. Notch proteins play an impo rtant role in cell fate determination in many different organisms and at di fferent stages of development, for example in mammalian T cell development. We therefore addressed whether structurally diverse gamma -secretase inhib itors impair Notch function by studying thymocyte development in marine fet al thymic organ cultures. Here we show that high concentrations of the most potent inhibitors blocked thymocyte development at the most immature stage . fn contrast, lower concentrations or less potent inhibitors impaired diff erentiation at a later stage, most notably suppressing the development of C D8 single-positive T cells. These phenotypes are consistent with an impairm ent of Notch signaling by gamma -secretase inhibitors and define a strict N otch dose dependence of consecutive stages during thymocyte development.