Expression patterns of astrocyte mRNA under numerous in vitro disease conditions and its applicability in drug development

星形胶质细胞 下调和上调 炎症 基因表达 信使核糖核酸 体外 脂多糖 颞叶皮质 小脑 生物 神经炎症 内分泌学 内科学 分子生物学 化学 基因 免疫学 医学 生物化学 神经科学 中枢神经系统
作者
Qiang Yue,Maggie Pui Man Hoi
出处
期刊:Alzheimers & Dementia [Wiley]
卷期号:19 (S21)
标识
DOI:10.1002/alz.071911
摘要

Abstract Background Reactive astrocytes have been observed surrounding amyloid beta (Aβ) plaques in Alzheimer’s disease (AD) patients and animal models. Researchers have pointed out the shortcomings of A1 and A2 classification. Our study aims to discuss the potentials of applying A1 and A2 genes in indicating astrocyte states and explore the relationship between inflammation‐related protein levels and A1 and A2 expression map under the treatment of human Aβ 1‐42 oligomer (hAβ 1‐42 O) and compound TBN. Method This study was conducted using murine astrocyte cell line (C8‐D1A). We compared the mRNAs levels (A1 and A2) under numerous in vitro disease conditions, including lipopolysaccharide (LPS) (800ng/ml), LPS‐induced microglial secretion, oxygen‐glucose deprivation (OGD), hAβ 1‐42 O (2.5μM), low glucose (11mM), high glucose (44mM) treatment. We also compared mRNA levels (cerebellum, cortex, and hippocampi) in high dose STZ (ip.) (150mg/kg, 4 weeks)‐induced C5BL/6 mouse brain, which is usually applied to as AD model. Furthermore, we explored the relationship between the A1, A2 expression map and inflammation‐related protein expression levels in C8‐D1A treated with hAβ 1‐42 O and TBN. Results A1 and A2 genes were altered in different patterns under numerous stimuli. Microglial secretion (LPS), LPS, OGD, hAβ 1‐42 O mostly induced mRNA upregulation, while abnormal glucose induced hypofunction of most genes. In STZ brain, mRNA expression exhibited district‐dependent differences. hippocampi mRNA were mostly activated compared to cerebellum and cortex, which indicated that Aβ plaque closely relates to astrocyte activation. In vitro, hAβ 1‐42 O upregulates inflammation related signal proteins. TBN inhibited hAβ 1‐42 O induced mRNA upregulation (A1, A2, C3, Il6, Tnfα, Tgfβ) and protein secretion (Il6, Tnfα). TBN could also inhibit LPS‐induced inflammation in astrocytes and increase mRNA levels of Aβ degrading enzymes (Ide, Ece‐1) . Conclusions It seems that there is not a strict paradigm of A1 and A2 mRNA expression to indicate astrocyte state and mRNA upregulation is not strictly related to detrimental effects. TBN exerted anti‐inflammatory effects may increase Aβ degrading activity. It also ameliorated inflammation induced by hAβ 1‐42 O, which may indicate the therapeutical potentials of targeting the activation of mRNA (S1pr3, Timp1, Hsbp1, Cxcl10, Osmr, Cp, Ligp1, Fkbp5, S100a10, slc10a6, B3gnt5) to ameliorate hAβ 1‐42 O‐induced astrocytic inflammation. Cp, Ligp1, Fkbp5, S100a10, slc10a6, B3gnt5).
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