Department of Anatomy, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
Department of Physiology, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
J Chem Neuroanat. 2019 Apr;97:71-79. doi: 10.1016/j.jchemneu.2019.02.002. Epub 2019 Feb 18.
Alzheimer's disease (AD) is characterized by a robust inflammatory response elicited by the accumulation and subsequently deposition of amyloid beta (Aβ) within the brain. The immune cells of brain migrate to and invest their processes within Aβ plaques and clear plaques from the brain. Previous studies have shown that treatment of myeloid cell with nuclear factor inhibitor increases expression of phagocytesis-related genes, such as triggering receptor expressed on myeloid cells 2 (TREM2). In myeloid cells, TREM2 has been involved in the regulation of phagocytosis, cell proliferation as well as inflammatory response in vitro. The purpose of this study was to further investigate microglial proliferation, phagocytosis and the expression of brain derived neurotrophic factor (BDNF) induced by up-regulation of TREM2 in Aβ1-42 injected mice. We first singly injected Aβ1-42 into the hippocampus of mice to build the model of AD-like symptoms. Subsequently, ammonium pyrrolidinedithiocarbamate (PDTC) was injected into the lateral ventricle of mice. Various immunohistochemical techniques and Western blot analyses were applied to examine expressions of TREM2, microglia, Aβ, Neuronal migration protein doublecortin (DCX) and BDNF in the hippocampus of mice. In the present study, we found the plaques-associated microglia lowly expressed TREM2 and BDNF in Aβ1-42 intra-hippocampal injected mice. Treatment of the models with a nuclear factor inhibitor, PDTC, further induced the expression of TREM2 and enhanced microglial phagocytosis, coincident with the rapid reduction in plaque burden. The expression of BDNF was up-regulated and the expression of DCX was partly restored. This means that up-regulation of TREM2 might induce the microglia to express the BDNF. These findings further indicate that the level of TREM2 may affect the microglia response to pathological process induced by Aβ.
阿尔茨海默病（AD）的特征是在大脑中淀粉样蛋白β（Aβ）的积累和随后沉积引起的强烈炎症反应。脑内免疫细胞迁移并在 Aβ 斑块内投入其过程，并从大脑中清除斑块。先前的研究表明，用核因子抑制剂处理髓样细胞会增加吞噬相关基因的表达，如髓样细胞表达的触发受体 2（TREM2）。在髓样细胞中，TREM2 参与了体外吞噬作用、细胞增殖以及炎症反应的调节。本研究的目的是进一步研究 TREM2 上调在 Aβ1-42 注射小鼠中诱导的小胶质细胞增殖、吞噬作用和脑源性神经营养因子（BDNF）的表达。我们首先将 Aβ1-42 单独注入小鼠海马，建立 AD 样症状模型。随后，将氨甲酰吡咯烷二硫代氨基甲酸盐（PDTC）注入小鼠侧脑室。应用各种免疫组织化学技术和 Western blot 分析来检测小鼠海马中 TREM2、小胶质细胞、Aβ、神经元迁移蛋白 doublecortin（DCX）和 BDNF 的表达。在本研究中，我们发现斑块相关的小胶质细胞在 Aβ1-42 海马内注射小鼠中低表达 TREM2 和 BDNF。用核因子抑制剂 PDTC 处理模型进一步诱导了 TREM2 的表达，并增强了小胶质细胞的吞噬作用，同时斑块负担迅速减少。BDNF 的表达上调，DCX 的表达部分恢复。这意味着 TREM2 的上调可能诱导小胶质细胞表达 BDNF。这些发现进一步表明，TREM2 的水平可能影响小胶质细胞对 Aβ 诱导的病理过程的反应。
