A31 The development of translational biomarkers of neuroinflammation in a mouse model of huntington’s disease

Laura Riggall, B. Siow, X. Golay, G. Bates
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Abstract

Background Currently, the concept of neuroinflammation includes inflammation associated with neurodegenerative diseases, in which there is little or no infiltration of blood-derived immune cells into the brain. However, the roles of brain-resident and peripheral immune cells in inflammatory settings are poorly understood, and neuroinflammation has not been well investigated in either Huntington’s disease (HD) patients or equivalent preclinical models. Aims This project aims to characterise the neuroinflammatory processes occurring in the R6/2 mouse model of HD over the time-course of the disease, using a number of molecular and cellular techniques in combination with in vivo imaging modalities (magnetic resonance spectroscopy [MRS] and magnetic resonance imaging [MRI]). Methods The R6/2 mouse expresses exon 1 of the human HTT gene, containing ˜180 CAGs. To begin undertaking a time-course analysis of the disease, immunohistochemistry (IHC) and western blotting were used in R6/2 and wild type (WT) mice between the ages of four- (pre-symptomatic) and 14-weeks-old (late-stage disease) to assess the neuroinflammatory processes in HD. Results Protocol optimisations to assess microglia and astrocytes (via their hallmark proteins IBA1 and GFAP respectively), two key cell types that mediate neuroinflammatory processes, have been performed for both western blotting and IHC. Subsequently, following their assessment in R6/2 mice, microglia and astrocytes were altered in terms of their reactivity, morphology and densities in comparison to WT controls. Conclusions The results of these investigations have begun to reveal changes in key neuroinflammatory cell types throughout the time-course of HD. In vivo imaging approaches and other molecular and cellular assessments will now be used to enable a more detailed characterisation of neuroinflammation in HD, and to identify robust, translational markers by which to track disease progression.
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在亨廷顿舞蹈病小鼠模型中神经炎症的翻译生物标志物的发展
目前,神经炎症的概念包括与神经退行性疾病相关的炎症,其中血液来源的免疫细胞很少或没有渗透到大脑中。然而,脑驻留和外周免疫细胞在炎症设置中的作用尚不清楚,神经炎症尚未在亨廷顿舞蹈病(HD)患者或同等临床前模型中得到很好的研究。该项目旨在利用多种分子和细胞技术结合体内成像方式(磁共振波谱[MRS]和磁共振成像[MRI]),描述HD R6/2小鼠模型在疾病时间过程中发生的神经炎症过程。方法R6/2小鼠表达人HTT基因外显子1,含~ 180 cag。为了开始进行疾病的时间过程分析,免疫组织化学(IHC)和western blotting在4周龄(症状前)和14周龄(疾病晚期)的R6/2和野生型(WT)小鼠中使用,以评估HD的神经炎症过程。结果:western blotting和IHC均对两种介导神经炎症过程的关键细胞类型——小胶质细胞和星形胶质细胞(分别通过其标志蛋白IBA1和GFAP)进行了方案优化。随后,在R6/2小鼠中进行评估后,与WT对照组相比,小胶质细胞和星形胶质细胞的反应性、形态和密度都发生了变化。这些研究的结果已经开始揭示在HD的整个时间过程中关键神经炎症细胞类型的变化。现在,体内成像方法和其他分子和细胞评估将用于更详细地描述HD患者的神经炎症,并确定可靠的翻译标记物,从而跟踪疾病进展。
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WED 253 An atypical presentation of sneddon syndrome H29 Practical tools and transfer aids in daily care for clients with advanced hd F06 When and how does manifest hd begin? a comparison of age at onset of motor and non-motor symptoms F33 Task-switching abilities in pre-manifest huntington’s disease subjects F56 Psychiatric symptoms in huntington’s disease: relationship to disease stage in the CAPIT-HD2 beta-testing study
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