gamma-Secretase modulators reduce endogenous amyloid beta(42) levels in human neural progenitor cells without altering neuronal differentiation

摘要

Soluble gamma-secretase modulators (SGSMs) selectively decrease toxic amyloid beta (A beta) peptides (A beta(42)). However, their effect on the physiologic functions of gamma-secretase has not been tested in human model systems. gamma-Secretase regulates fate determination of neural progenitor cells. Thus, we studied the impact of SGSMs on the neuronal differentiation of ReNcell VM (ReN) human neural progenitor cells (hNPCs). Quantitative PCR analysis showed that treatment of neurosphere-like ReN cell aggregate cultures with gamma-secretase inhibitors (GSIs), but not SGSMs, induced a 2- to 4-fold increase in the expression of the neuronal markers Tuj1 and doublecortin. GSI treatment also induced neuronal marker protein expression, as shown by Western blot analysis. In the same conditions, SGSM treatment selectively reduced endogenous A beta(42) levels by similar to 80. Mechanistically, we found that Notch target gene expressions were selectively inhibited by a GSI, not by SGSM treatment. We can assert, for the first time, that SGSMs do not affect the neuronal differentiation of hNPCs while selectively decreasing endogenous A beta(42) levels in the same conditions. Our results suggest that our hNPC differentiation system can serve as a useful model to test the impact of GSIs and SGSMs on both endogenous A beta levels and gamma-secretase physiologic functions including endogenous Notch signaling.