Department of Microbial and Biochemical Pharmacy, College of Pharmacy, Jinan University, Guangzhou, China.
Institute of Tropical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China.
Neuropharmacology. 2020 Dec 1;180:108304. doi: 10.1016/j.neuropharm.2020.108304. Epub 2020 Sep 12.
Amyloid-β (Aβ) accumulation is a pathological hallmark of Alzheimer's disease (AD). The receptor for advanced glycation end products (RAGE) is involved in the production and accumulation of Aβ. RP1, a peptide antagonist of RAGE, was screened by phage display technology in our previous studies, and its neuroprotective effects on an AD cell model have been confirmed. However, its efficacy in vivo remains unclear. Here, the intranasal delivery of RP1 to APPSwe/PS1dE9 (APP/PS1) mice significantly improved memory impairment and relieved the Aβ burden by decreasing the expression of amyloid precursor protein and β-secretase. RNA-sequencing (RNA-seq) was utilized to identify differentially expressed genes (DEGs) in APP/PS1 mice after RP1 administration. Several DEGs in RAGE downstream signalling pathways were downregulated. Some transcription factors (such as Fos) and the pathways enriched in the remarkable modules may also be related to the efficacy of RP1. In conclusion, RP1 significantly improves the AD symptoms of APP/PS1 mice, and the RNA-seq results provide new ideas for elucidating the possible mechanisms of RP1 treatment.
淀粉样蛋白-β（Aβ）的积累是阿尔茨海默病（AD）的病理标志。晚期糖基化终产物受体（RAGE）参与 Aβ的产生和积累。在我们之前的研究中，通过噬菌体展示技术筛选出 RAGE 的肽拮抗剂 RP1，并证实其对 AD 细胞模型具有神经保护作用。然而，其体内疗效尚不清楚。在这里，通过鼻腔内给予 RP1 治疗 APPswe/PS1dE9（APP/PS1）小鼠，可显著改善记忆障碍，并通过降低淀粉样前体蛋白和β-分泌酶的表达减轻 Aβ负担。使用 RNA 测序（RNA-seq）鉴定了 RP1 给药后 APP/PS1 小鼠中差异表达的基因（DEGs）。RAGE 下游信号通路中的几个 DEGs 下调。一些转录因子（如 Fos）和显著模块中富集的途径也可能与 RP1 的疗效有关。总之，RP1 可显著改善 APP/PS1 小鼠的 AD 症状，RNA-seq 结果为阐明 RP1 治疗的可能机制提供了新的思路。
