Piperine is a great lead compound, as a phytopharmaceutical with reported neuroprotective effects in neurodegenerative diseases. HJ105, a piperine derivative with high affinity to Keap1 receptor, attracts increasing attention in Alzheimer's disease (AD) treatment.This work mainly aimed to study HJ105's therapeutic effects on AβIn the in vivo part, a rat model of AD was established by bilateral intra-hippocampal administration of aggregated AβTreatment of HJ105 not only reversed memory impairment, but also protected neurons in the hippocampus by inhibiting Bax/Bcl2 ratio increase. HJ105 decreased TXNIP expression, suppressing NLRP3 inflammasome activation in the hippocampus, which in turn counteracted the upregulation of IL-1β and TNF-α. Notably, HJ105 exerted an inhibitory effect on Keap1-Nrf2 interaction and upregulated nuclear Nrf2, which conversely increased the expression levels of superoxide dismutase, catalase and glutathione peroxidase and downregulated malondialdehyde. Additionally, neurotoxicity induced by AβOverall, HJ105 exerts neuroprotective effects in SH-SY5Y cells induced by Aβ
