AZ1136 is a γ-secretase modulator that regulates amyloid-β ( Aβ ) production without reducing total Aβ generation. AZ1136 also modulates γ-secretase-mediated Notch S4 cleavage, but does not inhibit NICD formation. AZ1136 can be used in studies related to γ-secretase, APP processing and Alzheimer's disease [1] [2] [3].
In Vitro, AZ1136 (25 μM; 2 h) modulates γ-secretase-mediated APP processing in HEK/APPswe cell membranes, reduces the levels of Aβ42 and Aβ40, increases the levels of short-chain Aβ37 and Aβ38, alters specific short peptide cleavage products, and preferentially affects the turnover of Aβ42 without inhibiting the overall activity of γ-secretase[1]. AZ1136 modulates γ-secretase-mediated Aβ production in HEK/APPswe cells, potently reduces the levels of amyloidogenic Aβ42 (IC50 = 990 nM) and Aβ40 (IC50 = 1400 nM), while increasing the shorter, less amyloidogenic Aβ37 and Aβ39, without altering total Aβ levels[2]. AZ1136 (25 μM; 16 h) reduces Aβ40 and Aβ42 by 2.3-fold and 8.3-fold, respectively, increases Aβ37 and Aβ39 by 3.5-fold and 2.1-fold, respectively, in HEK/APPswe cells, while Aβ38 remains unaffected[2]. AZ1136 (5 h) modulates γ-secretase-mediated APP processing in HEK/APPswe cells, reduces the levels of Aβ42 (IC50 990 nM) and Aβ40 (IC50 1400 nM) (with higher potency against Aβ42), and increases the shorter Aβ37 and Aβ39 peptides, without altering total Aβ levels or inducing cytotoxicity[3]. AZ1136 (0-5 μM; 5 h) competes with AZ4800 for binding to a common molecular target in HEK/APPswe cells, indicating that both belong to the same class of second-generation γ-secretase modulators[3]. AZ1136 (2 h) retains Aβ-modulating activity in both HEK/APPswe-derived total membranes (TM) and carbonate-extracted membranes (CEM), significantly inhibiting Aβ42 and increasing Aβ37; a slight increase in Aβ38 is also observed in this cell-free membrane assay[3]. AZ1136 (25 μM; 24 h) modulates γ-secretase-mediated Notch N peptide production in HEK/FLAG-Notch1-ΔE cells, reducing F-N24 and F-N25 by 2.0-fold and 2.6-fold, respectively, and increasing F-N18 by 1.7-fold[2].
References:
[1]. Olsson F, et al. Characterization of intermediate steps in amyloid beta (Aβ) production under near-native conditions. The Journal of biological chemistry. 2014 Jan 17;289(3):1540-50.
[2]. Wanngren J, et al. Second generation γ-secretase modulators exhibit different modulation of Notch β and Aβ production. The Journal of biological chemistry. 2012 Sep 21;287(39):32640-50.
[3]. Borgegard T, et al. First and second generation γ-secretase modulators (GSMs) modulate amyloid-β (Aβ) peptide production through different mechanisms. The Journal of biological chemistry. 2012 Apr 06;287(15):11810-9.
In Vitro, AZ1136 (25 μM; 2 h) modulates γ-secretase-mediated APP processing in HEK/APPswe cell membranes, reduces the levels of Aβ42 and Aβ40, increases the levels of short-chain Aβ37 and Aβ38, alters specific short peptide cleavage products, and preferentially affects the turnover of Aβ42 without inhibiting the overall activity of γ-secretase[1]. AZ1136 modulates γ-secretase-mediated Aβ production in HEK/APPswe cells, potently reduces the levels of amyloidogenic Aβ42 (IC50 = 990 nM) and Aβ40 (IC50 = 1400 nM), while increasing the shorter, less amyloidogenic Aβ37 and Aβ39, without altering total Aβ levels[2]. AZ1136 (25 μM; 16 h) reduces Aβ40 and Aβ42 by 2.3-fold and 8.3-fold, respectively, increases Aβ37 and Aβ39 by 3.5-fold and 2.1-fold, respectively, in HEK/APPswe cells, while Aβ38 remains unaffected[2]. AZ1136 (5 h) modulates γ-secretase-mediated APP processing in HEK/APPswe cells, reduces the levels of Aβ42 (IC50 990 nM) and Aβ40 (IC50 1400 nM) (with higher potency against Aβ42), and increases the shorter Aβ37 and Aβ39 peptides, without altering total Aβ levels or inducing cytotoxicity[3]. AZ1136 (0-5 μM; 5 h) competes with AZ4800 for binding to a common molecular target in HEK/APPswe cells, indicating that both belong to the same class of second-generation γ-secretase modulators[3]. AZ1136 (2 h) retains Aβ-modulating activity in both HEK/APPswe-derived total membranes (TM) and carbonate-extracted membranes (CEM), significantly inhibiting Aβ42 and increasing Aβ37; a slight increase in Aβ38 is also observed in this cell-free membrane assay[3]. AZ1136 (25 μM; 24 h) modulates γ-secretase-mediated Notch N peptide production in HEK/FLAG-Notch1-ΔE cells, reducing F-N24 and F-N25 by 2.0-fold and 2.6-fold, respectively, and increasing F-N18 by 1.7-fold[2].
References:
[1]. Olsson F, et al. Characterization of intermediate steps in amyloid beta (Aβ) production under near-native conditions. The Journal of biological chemistry. 2014 Jan 17;289(3):1540-50.
[2]. Wanngren J, et al. Second generation γ-secretase modulators exhibit different modulation of Notch β and Aβ production. The Journal of biological chemistry. 2012 Sep 21;287(39):32640-50.
[3]. Borgegard T, et al. First and second generation γ-secretase modulators (GSMs) modulate amyloid-β (Aβ) peptide production through different mechanisms. The Journal of biological chemistry. 2012 Apr 06;287(15):11810-9.