Misfolded Truncated Protein τ Induces Innate Immune Response via MAPK Pathway
Misfolded Truncated Protein τ Induces Innate Immune Response via MAPK Pathway
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DOI：
10.4049/jimmunol.1100216
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发表时间：
2011-09-01
影响因子：
4.4
通讯作者：
Novak, Michal
中科院分区：
文献类型：
--
作者：
Kovac, Andrej;Zilka, Norbert;Novak, Michal
神经炎症在阿尔茨海默病和相关tau蛋白病的发病机制中起关键作用。我们以前已经表明，来自散发性阿尔茨海默病的非突变的人截短tau蛋白（151-391，4 R）的表达诱导转基因大鼠脑中伴随小胶质细胞和星形胶质细胞活化的神经元变性。本研究的目的是确定由错误折叠的截短tau蛋白诱导的先天免疫应答的分子机制。我们发现，纯化的重组截短的tau蛋白诱导小胶质细胞从静止到反应性表型的形态转化。同时，截短的tau蛋白导致NO、促炎细胞因子（IL-1 β、IL-6、TNF-α）和金属蛋白酶组织抑制剂-1从混合神经胶质细胞培养物中释放。值得注意的是，当用截短的tau蛋白激活纯的小胶质细胞培养物时，它显示出显着更高水平的促炎细胞因子，表明小胶质细胞在t介导的炎症反应中起关键作用。分子分析表明，截短的tau蛋白增加了三种MAPK（JNK，ERK 1，p38 β）和转录因子AP-1和NF-κ B的mRNA水平，最终导致IL-1 β，IL-6，TNF-α和NO的mRNA表达增强。因此，我们认为错误折叠的截短蛋白tau代表了阿尔茨海默病免疫治疗的可行靶点。免疫学杂志，2011，187：2732-2739。
Neuroinflammation plays a key role in the pathogenesis of Alzheimer's disease and related tauopathies. We have previously shown that expression of nonmutated human truncated tau (151-391, 4R), derived from sporadic Alzheimer's disease, induced neurofibrillary degeneration accompanied by microglial and astroglial activation in the brain of transgenic rats. The aim of the current study was to determine the molecular mechanism underlying innate immune response induced by misfolded truncated tau. We found that purified recombinant truncated tau induced morphological transformation of microglia from resting into the reactive phenotype. Simultaneously, truncated tau caused the release of NO, proinflammatory cytokines (IL-1 beta, IL-6, TNF-alpha), and tissue inhibitor of metalloproteinase-1 from the mixed glial cultures. Notably, when the pure microglial culture was activated with truncated tau, it displayed significantly higher levels of the proinflammatory cytokines, suggesting a key role of microglia in the t-mediated inflammatory response. Molecular analysis showed that truncated tau increased the mRNA levels of three MAPKs (JNK, ERK1, p38 beta) and transcription factors AP-1 and NF-kappa B that ultimately resulted in enhanced mRNA expression of IL-1 beta, IL-6, TNF-alpha, and NO. Our results showed for the first time, to our knowledge, that misfolded truncated protein tau is able to induce innate immune response via a MAPK pathway. Consequently, we suggest that misfolded truncated protein tau represents a viable target for immunotherapy of Alzheimer's disease. The Journal of Immunology, 2011, 187: 2732-2739.