A γ‐secretase inhibitor blocks Notch signaling in vivo and causes a severe neurogenic phenotype in zebrafish

Abstract

Inhibition of amyloid β-peptide (Aβ) production by blocking γ-secretase activity is at present one of the most promising therapeutic strategies to slow progression of Alzheimer's disease pathology. γ-secretase inhibitors apparently block Aβ generation via interference with presenilin (PS) function. Besides being an essential component of the γ-secretase complex, PS itself may be an aspartyl protease with γ-secretase activity, which is not only required for Aβ production but also for a similar proteolytic process involved in Notch signaling. Here we demonstrate that treatment of zebrafish embryos with a known γ-secretase inhibitor affects embryonic development in a manner indistinguishable from Notch signaling deficiencies at morphological, molecular and biochemical levels. This indicates severe side-effects of γ-secretase inhibitors in any Notch-dependent cell fate decision and demonstrates that the zebrafish is an ideal vertebrate system to validate compounds that selectively affect Aβ production, but not Notch signaling, under in vivo conditions.

Bile acids induce Delta-like 1 expression via Cdx2-dependent pathway in the development of Barrett's esophagus

“…20,21 To determine whether inactivation of Notch signaling by GSI affects the expression level of Dll1, we investigated the effects of DAPT on Dll1 mRNA expression in Het-1A, CP-A, and BAR-T cells and found that it increased endogenous Dll1 mRNA expression in a concentration-and time-dependent manner, peaking at 24 h (Figures 3a and b). Effective inhibition of Notch signaling was confirmed by expression of the intracellular-gamma-secretase cleaved Notch1 fragment using a specific antibody, as well as Hes1 and ATOH1 expression levels (Figures 3c and d).…”

Notch Activation Induces the Generation of Functional NK Cells from Human Cord Blood CD34-Positive Cells Devoid of IL-15

“…The absolute cell numbers with control Fc are ϳ5-fold higher than that with Delta4-Fc, and the fold increases in the cell number after the 3-wk culture were 45.7 Ϯ 31.6-fold (n ϭ 11). To confirm that the NK cell differentiation was Notch dependent, we added a ␥-secretase inhibitor, DAPT, which strongly inhibits ligand-dependent Notch activation (24,25). The cells cultured on Delta4-Fc-coated plates in the presence of DAPT had the same immunophenotype as those cultured on the control Fc-coated plates and did not give rise to NK cells (Fig.…”

cMyc-p53 feedback mechanism regulates the dynamics of T lymphocytes in the immune response

“…To test if this is a plausible mechanism for p53 induction in activated T cells, we first modulated cMyc expression through the indirect inhibition of Notch by DAPT, a g-secretase inhibitor. 37,24 Treatment with DAPT lowered cMyc levels and proliferation of activated T cells. 23 The cMyc target p14ARF was also downregulated in these cells.…”

“…23 In order to further study the regulatory interplay between cMyc and p53, we tested the effect of Notch inhibition by DAPT 24 (g secretase inhibitor) in activated T cells. This treatment lead to decreased T cell proliferation in a dose-dependent manner (Fig.…”