Effects of ibudilast treatment on hippocampal gene expression in Female Fisher transgenic 344-AD rats.

5 month old Female Fisher transgenic 344-AD (Tg-AD) rats expressing humanSwedishamyloid precursor protein (APPsw) and Δ exon 9 presenelin-1 (PS1ΔE9) were treated with Ibudilast (cat. no. HY-B0763, MCE) at 10 mg/kg body weight administered in rodent chow. Following 6 months of Ibudilast treatment, rats (11 months of age) were tested for cognitive behaviour prior to sacrificing. Hippocampal Brain region were dissected and RNA sequencing (RNAseq) analyses was done on the Isolated sample. Taken together we showed that Ibudilast treatment: (i) reduces inflammation by decreasing the levels of the pro inflammatory cytokine IL6, interferon receptor 1, the macrophage migration inhibitory factor (MIF), microglial associated proteins such as transmembrane protein 119 (TMEM119), arachidonate 5-lipoxygenase activating protein (Alox5ap), toll like receptor 7 (TLR7), lysosomal protein transmembrane 5 (LAPTM5) and triggering receptor expressed on myeloid cells 2 (TREM2); (ii) increases expression of synaptic proteins such as synaptotagmin 2 (SYT2), which regulates vesicular transport, syntaxins (STX), which participates in neurotransmitter release, and cadherin (CDH1), which maintains synapse structure; and (iii) reduces the expression of the neurotrophic factor BDNF by 2-fold in both male and female treated rats.5月龄雌性Fisher转基因344-AD（Tg-AD）大鼠，该模型表达人瑞典突变淀粉样前体蛋白（APPsw）与Δ外显子9早老素1（PS1ΔE9）。将异丁司特（Ibudilast，货号HY-B0763，MCE）以10mg/kg体重的剂量掺入啮齿类动物饲料中给药。经过6个月的异丁司特给药后，对11月龄的大鼠开展认知行为学测试，随后实施安乐死。解剖获取海马脑区，对分离得到的样本进行RNA测序（RNAseq）分析。本研究综合结果显示，异丁司特给药可产生如下效应：（i）减轻炎症反应：降低促炎细胞因子IL6、干扰素受体1、巨噬细胞移动抑制因子（MIF）以及小胶质细胞相关蛋白的水平，包括跨膜蛋白119（TMEM119）、花生四烯酸5-脂氧合酶激活蛋白（Alox5ap）、Toll样受体7（TLR7）、溶酶体蛋白跨膜5（LAPTM5）与髓系细胞触发受体2（TREM2）；（ii）上调突触相关蛋白的表达：包括调控囊泡运输的突触结合蛋白2（SYT2）、参与神经递质释放的突触融合蛋白（STX）以及维持突触结构的钙黏蛋白（CDH1）；（iii）在雌雄给药大鼠中，均使脑源性神经营养因子（BDNF）的表达下调2倍。