The machinery of γ-secretase inhibitor alleviated cognitive deficits and neuropathology in APP/PS1 transgenic mice

Abstract

γ-secretase inhibitor is associated with Alzheiner’s disease (AD). Since crenigacestat is a gamma-secretase inhibitor, it has been extensively studied in preclinical models and clinical trials of cancer prevention due to it as a γ-secretase inhibitor. However, the possible involvement of crenigacestat in progression of AD remains unknown. This study found that crenigacestat treatment attenuated neurological impairment in AD mice. Moreover, treatment with crenigacestat decreased the level of insoluble and soluble Aβ and attenuated the apoptosis of neuron in hippocampus of AD mice. We also found that crenigacestat significantly inhibited the activation of microglia and neuron inflammation of hippocampus of AD mice. Finally, we explored the mechanism of crenigacestat suppressed the progression of AD, we found that crenigacestat significantly inhibited Notch signaling pathway, which suppressed the PI3K and mTOR signaling pathway. Collectively, these findings indicated that crenigacestat can suppressed the progression of AD by suppressing Notch signaling pathway, which blocking PI3K/PBK/mTOR signaling pathway.