The γ-secretase modulator CHF5074 restores memory and hippocampal synaptic plasticity in plaque-free Tg2576 mice

The study goal is to investigate the effects of CHF5074, a NSAID derivative in which the cyclo-oxygenase activity has been removed and inhibitory activity of Aβ production potentiated, on Aβ production in young AD Tg2576 mice that have no plaque deposition. CHF5074 has previously been shown to act as a γ-secretase modulator in adult Tg mice by binding APP and decreasing Aβ production and plaque deposition with no effect on Notch intracellular cleavage. The principal findings in this study include contextual memory impairment attenuation after acute subcutaneous administration at 5 months and recognition memory impairment reversal after 4-week chronic treatment at 6 months, both associated with LTP impairment reversal in the hippocampus. There was a significant reduction of intraneuronal Aβ and hyperphosphorylated tau, but no change in soluble or oligomeric Aβ. This study shows beneficial effects of CHF5074 treatment on young Tg mice before plaque formation.