E 2012

E2012 is a modulator of γ-secretase.¹ It selectively inhibits APP intracellular signaling domain (AICD) cleavage to amyloid-β (Aβ) over Notch cleavage to its signaling effector Notch intracellular domain (NICD), processes both mediated by γ-secretase, when used at a concentration of 1 ?M in luciferase assays.² E2012 also inhibits the activity of the cholesterol synthesis enzyme 3β-hydroxysterol ?²⁴-reductase (DHCR24) in primary rat hepatocytes and HepG2 cells (IC₅₀s = 11 and 15 nM, respectively).³ It reduces Aβ (1-42) (Aβ42) production in primary rat embryonic cerebral cortex neurons with an IC₅₀ value of 220 nM.⁴ E2012 (100 mg/kg) also decreases Aβ42 levels in guinea pig brain and cerebral spinal fluid (CSF).⁴

1.Hahn, S., Brüning, T., Ness, J., et al.Presenilin-1 but not amyloid precursor protein mutations present in mouse models of Alzheimer's disease attenuate the response of cultured cells to γ-secretase modulators regardless of their potency and structureJ. Neurochem.116(3)385-395(2011) 2.Dimitrov, M., Alattia, J.-R., Lemmin, T., et al.Alzheimer's disease mutations in APP but not γ-secretase modulators affect epsilon-cleavage-dependent AICD productionNat. Commun.4:2246(2013) 3.Nakano-Ito, K., Fujikawa, Y., Hihara, T., et al.E2012-induced cataract and its predictive biomarkersToxicol. Sci.137(1)249-258(2014) 4.Kimura, T., Kawano, K., Doi, E., et al.Cinnamide compound(2005)