作者列表：Xu Chong, Mei Yilan, Yang Ruihan, Luo Qiudan, Zhang Jienian, Kou Xiaolin, Hu Jianfeng, Wang Yujie, Li Yue, Chen Rong, Zhang Zhengping, Yao Yuyuan, Sima Jian

发表时间：2024-4-

期刊：Cell ａnd Bioscience

影响因子：6.1

DOI:10.1186/s13578-024-01230-8

Abstract

Background

Alzheimer’s disease （AD） is the most prevalent neurodegenerative disease with limited disease-modifying treatments. Drug repositioning strategy has now emerged as a promising approach for anti-AD drug discovery. Using 5×FAD mice ａnd Aβ-treated neurons in culture, we tested the efficacy of Y-2, a compounded drug containing the antioxidant Edaravone （Eda）, a pyrazolone ａnd （+）-Borneol, an anti-inflammatory diterpenoid from cinnamon, approved for use in amyotrophic lateral sclerosis patients.

 

Results

We examined effects of Y-2 versus Eda alone by i.p. administered in 8-week-old 5×FAD mice （females） for 4 months by comparing cognitive function, Aβ pathologies, neuronal necroptosis ａnd neuroinflammation. Using primary neurons ａnd astrocytes, as well as neuronal ａnd astrocytic cell lines, we elucidated the molecular mechanisms of Y-2 by examining neuronal injury, astrocyte-mediated inflammation ａnd necroptosis. Here, we find that Y-2 improves cognitive function in AD mice. Histopathological data show that Y-2, better than Eda alone, markedly ameliorates Aβ pathologies including Aβ burden, astrogliosis/microgliosis, ａnd Tau phosphorylation. In addition, Y-2 reduces Aβ-induced neuronal injury including neurite damage, mitochondrial impairment, reactive oxygen species production ａnd NAD+ depletion. Notably, Y-2 inhibits astrocyte-mediated neuroinflammation ａnd attenuates TNF-α-triggered neuronal necroptosis in cell cultures ａnd AD mice. RNA-seq further demonstrates that Y-2, compared to Eda, indeed upregulates anti-inflammation pathways in astrocytes.