研究SAA在外周炎症诱导小鼠脑内Aβ及Tau蛋白异常聚集中的重要作用

Alzheimer's disease (AD) is a severe neurodegenerative disease of the central nervous system, of which the pathogenesis is not very clear. Our previous experiment found that acute peripheral inflammation induced inflammatory response in mice brain, and the transcription levels of acute phase protein SAA and Tau phosphorylation were significantly increased. Therefore, we propose that peripheral inflammation is one of the major pathogenetic factors of AD, and SAA plays a key role in this process: Acute or chronic peripheral inflammation causes acute phase response in brain, such as the release of cytokines and the transcriptional expression of SAA; SAA further induces the accumulation of Aβ and Tau hyperphosphorylation in neuron by activating microglia and/or astrocytes indirectly, or a direct role on neuron. Based on our previous work, a murine model of chronic inflammation will be established in here to verify that if peripheral inflammation could continuely induce the expression of SAA, Aβ accumulation and Tau hyperphosphorylation in mice brain, and if microglia and/or astrocytes could be activated; by comparing the results of acute and/or chronic inflammation model by using SAA gene knock-out mice and SAA transgenic mice with the results of the WT mice, to determine the key role of SAA on the induction of Aβ accumulation and Tau hyperphosphorylation in brain; finally, the mechanism of SAA will be further explored in vitro by using the primary cell culture system.

阿尔茨海默病（AD）是一种中枢神经系统退行性疾病。目前，AD发病机制尚不完全清楚。我们前期实验发现急性外周炎症引起小鼠脑内炎症反应，急性时相反应蛋白SAA转录水平及Tau磷酸化水平显著增加。因此，我们提出"外周炎症是AD发生的主要诱因之一"假说，而SAA在这一过程中起关键作用：外周急慢性炎症引起脑内的急性时相反应，诱导炎症因子释放及SAA转录表达，高表达的SAA能间接的通过激活小胶质细胞及星形胶质细胞，或直接作用于神经元诱导Aβ及Tau聚集，产生AD症状。本项目在前期工作基础上，建立小鼠慢性炎症模型，验证外周炎症是否能持续诱导脑内SAA高表达，小胶质细胞及星形胶质细胞是否被激活，小鼠AD症状是否持续存在；同时比较SAA基因敲除及SAA转基因小鼠急慢性炎症模型，确定SAA在外周炎症诱导AD发生中所起的关键作用；最后，在原代细胞水平验证SAA的作用机制，为AD的预防及治疗提供新的方法及靶点。

阿尔茨海默病（AD）是一种中枢神经系统退行性疾病。目前，AD发病机制尚不完全清楚。我们实验发现急性外周炎症引起小鼠脑内炎症反应，急性时相反应蛋白SAA转录水平及Tau磷酸化水平显著增加。因此，我们提出“外周炎症是AD发生的主要诱因之一”假说，而SAA在这一过程中起关键作用。本项目在前期工作基础上，建立了Saa3基因敲除小鼠和Saa3转基因小鼠模型，证实Saa3敲除能够增加LPS诱导的tau蛋白磷酸化，而高表达Saa3则降低LPS诱导的tau蛋白磷酸化。且脑注射SAA也能够降低tau蛋白磷酸化。这些结果说明Saa3能够在基础水平和病理水平降低tau蛋白的磷酸化，对神经元起到保护的作用。并且通过机制研究，即采用原代培养的小胶质细胞和神经元及脑注射IL-10抗体，我们发现Saa3是通过激活小胶质细胞释放IL-10，抑制神经元内tau蛋白的过度磷酸化。因此，我们的研究结果为AD的预防及治疗提供了新的潜在的靶点。