Microglial TYROBP/DAP12 in Alzheimer's disease: Transduction of physiological and pathological signals across TREM2.
Microglial TYROBP/DAP12 in Alzheimer's disease: Transduction of physiological and pathological signals across TREM2.
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DOI：
10.1186/s13024-022-00552-w
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发表时间：
2022-08-24
影响因子：
15.1
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中科院分区：
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TYROBP（也称为DAP 12或KARAP）是一种跨膜衔接蛋白，最初被描述为自然杀伤（NK）细胞的受体激活亚基组分。TYROBP在许多细胞类型中表达，包括外周血单核细胞、巨噬细胞、树突状细胞和破骨细胞，但最近关注的一个关键点与TYROBP在小胶质细胞质膜上表达的许多受体的功能中发挥的关键作用有关。TYROBP是参与阿尔茨海默病（AD）的几种受体的下游衔接子和推定的信号传导伴侣，包括SIRP 1 β、CD 33、CR 3和TREM 2。TYROBP由于其通过跨越这些受体的信号转导在脑内稳态中的重要性而获得了其目前的大部分恶名。在这篇综述中，我们提供了一个概述的证据表明，TYROBP的生物学扩展超出其相互作用与这四个配体结合的胞外域-膜内结构域分子。除了回顾TYROBP的结构和定位，我们讨论了我们最近的进展，无论是脑淀粉样变性或tau蛋白病的小鼠模型，被改造为TYROBP缺陷或TYROBP过表达。值得注意的是，组成型TYROBP缺陷小鼠提供了一个模型的遗传弹性的任何一个定义的蛋白质病变的AD。学习行为和突触电生理功能保持在正常的生理水平，即使面对严重的脑淀粉样变性（APP/PSEN 1;Tyrobp−/−小鼠）或tau蛋白病（MAPTP 301 S;Tyrobp−/−小鼠）。与每种蛋白质型相关的功能性突触功能障碍的基本基础是补体C1 q的积累。TYROBP缺乏阻止了与任一蛋白质病相关的C1 q积累。基于这些数据，我们推测TYROBP在小胶质细胞感觉体和疾病相关小胶质细胞（DAM）表型的出现中起关键作用。TYROBP也可能在突触完整性标志物的丧失中起关键作用（例如，突触素样免疫反应性），其长期以来被认为是与并发临床认知功能最密切相关的人AD分子神经病理学的特征。
TYROBP (also known as DAP12 or KARAP) is a transmembrane adaptor protein initially described as a receptor-activating subunit component of natural killer (NK) cells. TYROBP is expressed in numerous cell types, including peripheral blood monocytes, macrophages, dendritic cells, and osteoclasts, but a key point of recent interest is related to the critical role played by TYROBP in the function of many receptors expressed on the plasma membrane of microglia. TYROBP is the downstream adaptor and putative signaling partner for several receptors implicated in Alzheimer’s disease (AD), including SIRP1β, CD33, CR3, and TREM2. TYROBP has received much of its current notoriety because of its importance in brain homeostasis by signal transduction across those receptors. In this review, we provide an overview of evidence indicating that the biology of TYROBP extends beyond its interaction with these four ligand-binding ectodomain-intramembranous domain molecules. In addition to reviewing the structure and localization of TYROBP, we discuss our recent progress using mouse models of either cerebral amyloidosis or tauopathy that were engineered to be TYROBP-deficient or TYROBP-overexpressing. Remarkably, constitutively TYROBP-deficient mice provided a model of genetic resilience to either of the defining proteinopathies of AD. Learning behavior and synaptic electrophysiological function were preserved at normal physiological levels even in the face of robust cerebral amyloidosis (in APP/PSEN1;Tyrobp−/− mice) or tauopathy (in MAPTP301S;Tyrobp−/− mice). A fundamental underpinning of the functional synaptic dysfunction associated with each proteotype was an accumulation of complement C1q. TYROBP deficiency prevented C1q accumulation associated with either proteinopathy. Based on these data, we speculate that TYROBP plays a key role in the microglial sensome and the emergence of the disease-associated microglia (DAM) phenotype. TYROBP may also play a key role in the loss of markers of synaptic integrity (e.g., synaptophysin-like immunoreactivity) that has long been held to be the feature of human AD molecular neuropathology that most closely correlates with concurrent clinical cognitive function.
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影响因子：
11.2
作者：
Butovsky, Oleg;Jedrychowski, Mark P.;Cialic, Ron;Krasemann, Susanne;Murugaiyan, Gopal;Fanek, Zain;Greco, David J.;Wu, Pauline M.;Doykan, Camille E.;Kiner, Olga;Lawson, Robert J.;Frosch, Matthew P.;Pochet, Nathalie;El Fatimy, Rachid;Krichevsky, Anna M.;Gygi, Steven P.;Lassmann, Hans;Berry, James;Cudkowicz, Merit E.;Weiner, Howard L.
通讯作者：
Weiner, Howard L.
影响因子：
4.3
作者：
Angata, Takashi;Tabuchi, Yukako;Nakamura, Mitsuru
通讯作者：
Nakamura, Mitsuru
影响因子：
4.4
作者：
Aguilar, H;Alvarez-Errico, D;López-Botet, M
通讯作者：
López-Botet, M
影响因子：
4.4
作者：
Chung, DH;Humphrey, MB;Daws, MR
通讯作者：
Daws, MR
影响因子：
4.4
作者：
Daws, MR;Sullam, PM;Seaman, WE
通讯作者：
Seaman, WE