Nitazoxanide, an anti-parasitic drug, efficiently ameliorates learning and memory impairments in AD model mice

摘要

The pathogenesis of Alzheimer's disease (AD) is characterized by both accumulation of β-amyloid (Aβ) plaque and formation of neurofibrillary tangles in the brain.Recent evidence shows that autophagy activation may potently promote intracellular Aβ clearance.Thus targeting autophagy becomes a promising strategy for discovery of drug leads against AD.In the present study,we established a platform to discover autophagy stimulator and screened the lab in-house FDA-approved drug library.We found that anti-parasitic drug nitazoxanide (NTZ) was an autophagy activator and could efficiently improve learning and memory impairments in APP/PS1 transgenic mice.In BV2 cells and primary cortical astrocytes,NTZ stimulated autophagy and promoted Aβ clearance by inhibiting both PI3K/AKT/mTOR/ULK1 and NQO1/mTOR/ULK1 signaling pathways;NTZ treatment attenuated LPS-induced inflammation by inhibiting PI3K/AKT/IkB/NFKB signaling.In SH-SY5Y cells and primary cortical neurons,NTZ treatment restrained tau hyperphosphorylation through inhibition of PI3K/AKT/GSK3β pathway.The beneficial effects and related signaling mechanisms from the in vitro studies were also observed in APP/PS1 transgenic mice following administration of NTZ (90 mg·kg-1·d-1,ig) for 100 days.Furthermore,NTZ administration decreased Aβ level and senile plaque formation in the hippocampus and cerebral cortex of APP/PS1 transgenic mice,and improved learning and memory impairments in Morris water maze assay.In conclusion,our results highlight the potential of NTZ in the treatment of AD.