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Deficiency of TYROBP, an adapter protein for TREM2 and CR3 receptors, is neuroprotective in a mouse model of early Alzheimer’s pathology
Acta Neuropathologica ( IF 12.7 ) Pub Date : 2017-06-13 , DOI: 10.1007/s00401-017-1737-3
Jean-Vianney Haure-Mirande , Mickael Audrain , Tomas Fanutza , Soong Ho Kim , William L. Klein , Charles Glabe , Ben Readhead , Joel T. Dudley , Robert D. Blitzer , Minghui Wang , Bin Zhang , Eric E. Schadt , Sam Gandy , Michelle E. Ehrlich

Conventional genetic approaches and computational strategies have converged on immune-inflammatory pathways as key events in the pathogenesis of late onset sporadic Alzheimer’s disease (LOAD). Mutations and/or differential expression of microglial specific receptors such as TREM2, CD33, and CR3 have been associated with strong increased risk for developing Alzheimer’s disease (AD). DAP12 (DNAX-activating protein 12)/TYROBP, a molecule localized to microglia, is a direct partner/adapter for TREM2, CD33, and CR3. We and others have previously shown that TYROBP expression is increased in AD patients and in mouse models. Moreover, missense mutations in the coding region of TYROBP have recently been identified in some AD patients. These lines of evidence, along with computational analysis of LOAD brain gene expression, point to DAP12/TYROBP as a potential hub or driver protein in the pathogenesis of AD. Using a comprehensive panel of biochemical, physiological, behavioral, and transcriptomic assays, we evaluated in a mouse model the role of TYROBP in early stage AD. We crossed an Alzheimer’s model mutant APP KM670/671NL /PSEN1 Δexon9 (APP/PSEN1) mouse model with Tyrobp / mice to generate AD model mice deficient or null for TYROBP (APP/PSEN1; Tyrobp +/ or APP/PSEN1; Tyrobp /). While we observed relatively minor effects of TYROBP deficiency on steady-state levels of amyloid-β peptides, there was an effect of Tyrobp deficiency on the morphology of amyloid deposits resembling that reported by others for Trem2 / mice. We identified modulatory effects of TYROBP deficiency on the level of phosphorylation of TAU that was accompanied by a reduction in the severity of neuritic dystrophy. TYROBP deficiency also altered the expression of several AD related genes, including Cd33. Electrophysiological abnormalities and learning behavior deficits associated with APP/PSEN1 transgenes were greatly attenuated on a Tyrobp-null background. Some modulatory effects of TYROBP on Alzheimer’s-related genes were only apparent on a background of mice with cerebral amyloidosis due to overexpression of mutant APP/PSEN1. These results suggest that reduction of TYROBP gene expression and/or protein levels could represent an immune-inflammatory therapeutic opportunity for modulating early stage LOAD, potentially leading to slowing or arresting the progression to full-blown clinical and pathological LOAD.



中文翻译:

TYROBP是TREM2和CR3受体的衔接蛋白,在早期阿尔茨海默氏病小鼠模型中具有神经保护作用

常规的遗传方法和计算策略已经集中在免疫炎症途径上,这是迟发性散发性阿尔茨海默病(LOAD)发病机理中的关键事件。小胶质细胞特异性受体(如TREM2,CD33和CR3)的突变和/或差异表达与罹患阿尔茨海默氏病(AD)的风险大大增加有关。DAP12(DNAX激活蛋白12)/ TYROBP(一种定位于小胶质细胞的分子)是TREM2,CD33和CR3的直接伴侣/适配器。我们和其他人以前已经证明TYROBP表达在AD患者和小鼠模型中增加。此外,TYROBP编码区的错义突变最近在一些AD患者中发现了这种疾病。这些证据以及对LOAD脑基因表达的计算分析表明,DAP12 / TYROBP是AD发病机理中的潜在枢纽或驱动蛋白。使用生物化学,生理学,行为学和转录组学分析的综合小组,我们在小鼠模型中评估了TYROBP在早期AD中的作用。我们穿过阿尔茨海默氏模型突变体APP KM670 / 671NL / PSEN1 Δexon9(APP / PSEN1)与小鼠模型TYROBP - / -小鼠以产生AD模型小鼠缺陷或者为null TYROBP(APP / PSEN1; TYROBP + / -APP / PSEN1;泰罗普- / -)。尽管我们观察到TYROBP缺乏对淀粉样β肽稳态水平的影响相对较小,但Tyrobp缺乏对淀粉样沉积物形态的影响类似于其他人对Trem2 - / -小鼠的报道。我们发现TYROBP缺乏对TAU磷酸化水平的调节作用,伴随着神经营养不良的严重性降低。TYROBP缺乏症还改变了一些与AD相关的基因的表达,包括Cd33。在Tyrobp上,与APP / PSEN1转基因相关的电生理异常和学习行为缺陷得到了极大的缓解空背景。TYROBP对阿尔茨海默氏症相关基因的某些调节作用仅在突变型APP / PSEN1过表达的脑淀粉样变性小鼠的背景下才可见。这些结果表明,TYROBP基因表达和/或蛋白质水平的降低可能代表了调节早期LOAD的免疫炎症治疗机会,可能导致减缓或阻止进展为成熟的临床和病理学LOAD的进程。

更新日期:2017-06-13
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