NGP-555

NGP-555 is a modulator of γ-secretase that inhibits APP intracellular signaling domain (AICD) cleavage to amyloid-β (Aβ; IC₅₀s = 531 and 131 nM for Aβ40 and Aβ42, respectively, in HeLa cell membranes).¹ It is selective for AICD cleavage to Aβ over E-cadherin and Notch cleavage to their signaling effectors, E-cadherin γ-C-terminal fragment and NICD, respectively, processes also mediated by γ-secretase, when used at a concentration of 30 µM. Dietary administration of NGP-555 (~50 mg/kg per day) reduces cortical and hippocampal plaque area in the Tg2576 transgenic mouse model of Alzheimer's disease.¹ NGP-555 (25 mg/kg per day, p.o.) decreases plasma and brain Aβ40 and Aβ42 levels, as well as increases spontaneous alternations in the Y-maze, indicating prevention of memory deficits, in Tg2576 mice.²

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1. Kounnas, M.Z., Danks, A.M., Cheng, S., et al. Modulation of γ-secretase reduces β-amyloid deposition in a transgenic mouse model of Alzheimer’s disease. Neuron 67(5), 769-780 (2010).

2. Kounnas, M.Z., Lane-Donovan, C., Nowakowski, D.W., et al. NGP 555, a γ-secretase modulator, lowers the amyloid biomarker, Aβ42, in cerebrospinal fluid while preventing Alzheimer’s disease cognitive decline in rodents. Alzheimers Dement. TRCI 3(1), 65-73 (2017).