Integrative approach to sporadic Alzheimer's disease: deficiency of TYROBP in cerebral Aβ amyloidosis mouse normalizes clinical phenotype and complement subnetwork molecular pathology without reducing Aβ burden
Integrative approach to sporadic Alzheimer's disease: deficiency of TYROBP in cerebral Aβ amyloidosis mouse normalizes clinical phenotype and complement subnetwork molecular pathology without reducing Aβ burden
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DOI：
10.1038/s41380-018-0255-6
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发表时间：
2019-03-01
影响因子：
11
通讯作者：
Ehrlich, Michelle E.
中科院分区：
文献类型：
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作者：
Haure-Mirande, Jean-Vianney;Wang, Minghui;Ehrlich, Michelle E.
综合基因网络方法使探索的新途径，牵连的因果基因在散发性晚发性阿尔茨海默病（LOAD）的发病机制，从而提供新的见解药物发现计划。我们之前构建了一个偶发性LOAD的概率因果网络模型，并确定了TYROBP/DAP 12，编码小胶质细胞跨膜信号多肽和TREM 2的直接接头，作为网络中最强大的关键驱动基因。在这里，我们发现在AD型脑A β淀粉样变性小鼠模型中TYROBP/DAP 12的缺失，（APP（KM670/671NL）/PSEN1（Δ外显子9））通过使APP/PSEN 1小鼠的转录组正常化并抑制参与从稳态小胶质细胞向疾病相关小胶质细胞（DAM）转换的基因的诱导，包括Trem 2、补体C1（C1）、C2（C2）、C3（C3）和C4（C4），概括了预期的网络特征。（C1 qa、C1 qb、C1 qc和Itgax）、Clec 7a和Cst 7。重要的是，我们表明，在淀粉样变性小鼠模型中TYROBP/DAP 12的组成性缺失阻止了与APP（KM 670/671 NL）/PSEN 1（Delta外显子9）小鼠表型相关的电生理和学习行为改变的出现。我们的研究结果表明，TYROBP/DAP 12可以代表一种新的治疗靶点，以减缓，阻止或预防偶发性LOAD的发展。这些数据表明，在死后人类LOAD脑中观察到的网络病理学可以在遗传操作的小鼠脑中忠实地再现。这些数据还通过展示网络如何与LOAD的标准神经病理学特征相交来验证我们的多尺度基因网络。
Integrative gene network approaches enable new avenues of exploration that implicate causal genes in sporadic late-onset Alzheimer's disease (LOAD) pathogenesis, thereby offering novel insights for drug-discovery programs. We previously constructed a probabilistic causal network model of sporadic LOAD and identified TYROBP/DAP12, encoding a microglial transmembrane signaling polypeptide and direct adapter of TREM2, as the most robust key driver gene in the network. Here, we show that absence of TYROBP/DAP12 in a mouse model of AD-type cerebral A beta amyloidosis (APP(KM670/671NL)/PSEN1(Delta exon9)) recapitulates the expected network characteristics by normalizing the transcriptome of APP/PSEN1 mice and repressing the induction of genes involved in the switch from homeostatic microglia to disease-associated microglia (DAM), including Trem2, complement (C1qa, C1qb, C1qc, and Itgax), Clec7a and Cst7. Importantly, we show that constitutive absence of TYROBP/DAP12 in the amyloidosis mouse model prevented appearance of the electrophysiological and learning behavior alterations associated with the phenotype of APP(KM670/671NL)/PSEN1(Delta exon9) mice. Our results suggest that TYROBP/DAP12 could represent a novel therapeutic target to slow, arrest, or prevent the development of sporadic LOAD. These data establish that the network pathology observed in postmortem human LOAD brain can be faithfully recapitulated in the brain of a genetically manipulated mouse. These data also validate our multiscale gene networks by demonstrating how the networks intersect with the standard neuropathological features of LOAD.