Dystrophic neuronal processes harboring neuritic plaque (NP) tau pathology are found in association with Aβ plaques in Alzheimer’s disease (AD) brain. Microglia are also in proximity to these plaques and microglial gene variants are known risk factors in AD, including loss-of-function variants of TREM2. We have further investigated the role of Aβ plaque-associated microglia in 5XFAD mice in which NP tau pathology forms after intracerebral injection of AD brain-derived pathologic tau (AD-tau), focusing on the consequences of reduced TREM2 expression and microglial depletion after treatment with the colony-stimulating factor 1 (CSFR1) inhibitor, PLX3397. Young 5XFAD mice treated with PLX3397 had a large reduction of brain microglia, including cortical plaque-associated microglia, with a significant reduction of Aβ plaque burden in the cortex. A corresponding decrease in cortical APP-positive dystrophic processes and NP tau pathology were observed after intracerebral AD-tau injection in the PLX3397-treated 5XFAD mice. Consistent with prior reports, 5XFAD × TREM2−/− mice showed a significant reduction of plaque-associated microglial, whereas 5XFAD × TREM2+/− mice had significantly more plaque-associated microglia than 5XFAD × TREM2−/− mice. Nonetheless, AD-tau injected 5XFAD × TREM2+/− mice showed greatly increased AT8-positive NP tau relative to 5XFAD × TREM2+/+ mice. Expression profiling revealed that 5XFAD × TREM2+/− mice had a disease-associated microglial (DAM) gene expression profile in the brain that was generally intermediate between 5XFAD × TREM2+/+ and 5XFAD × TREM2−/− mice. Microarray analysis revealed significant differences in cortical and hippocampal gene expression between AD-tau injected 5XFAD × TREM2+/− and 5XFAD × TREM2−/− mice, including pathways linked to microglial function. These data suggest there is not a simple correlation between the extent of microglia plaque interaction and plaque-associated neuritic damage. Moreover, the differences in gene expression and microglial phenotype between TREM2+/− and TREM2−/− mice suggest that the former may better model the single copy TREM2 variants associated with AD risk.

中文翻译：

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小胶质细胞耗竭和 TREM2 缺陷对 5XFAD 小鼠 Aβ 斑块负荷和神经炎斑块 tau 病理学的影响

发现含有神经炎斑块 (NP) tau 病理学的营养不良性神经元过程与阿尔茨海默病 (AD) 大脑中的 Aβ 斑块相关。小胶质细胞也靠近这些斑块，小胶质细胞基因变异是 AD 的已知危险因素，包括 TREM2 的功能丧失变异。我们进一步研究了 Aβ 斑块相关小胶质细胞在 5XFAD 小鼠中的作用，其中脑内注射 AD 脑源性病理性 tau (AD-tau) 后形成 NP tau 病理，重点关注治疗后 TREM2 表达减少和小胶质细胞耗竭的后果与集落刺激因子 1 (CSFR1) 抑制剂 PLX3397 一起使用。用 PLX3397 治疗的年轻 5XFAD 小鼠的大脑小胶质细胞大量减少，包括皮质斑块相关的小胶质细胞，同时皮质中的 Aβ 斑块负荷显着减少。在 PLX3397 治疗的 5XFAD 小鼠脑内注射 AD-tau 后，观察到皮质 APP 阳性营养不良过程和 NP tau 病理学相应减少。与之前的报道一致，5XFAD × TREM2−/− 小鼠显示斑块相关小胶质细胞显着减少，而 5XFAD × TREM2+/- 小鼠的斑块相关小胶质细胞明显多于 5XFAD × TREM2−/− 小鼠。尽管如此，相对于 5XFAD × TREM2+/+ 小鼠，注射 AD-tau 的 5XFAD × TREM2+/- 小鼠显示 AT8 阳性 NP tau 大大增加。表达谱显示，5XFAD × TREM2+/- 小鼠大脑中的疾病相关小胶质细胞 (DAM) 基因表达谱通常介于 5XFAD × TREM2+/+ 和 5XFAD × TREM2−/− 小鼠之间。微阵列分析显示，注射 AD-tau 的 5XFAD × TREM2+/- 小鼠和 5XFAD × TREM2−/− 小鼠之间的皮质和海马基因表达存在显着差异，包括与小胶质细胞功能相关的通路。这些数据表明小胶质细胞斑块相互作用的程度与斑块相关的神经炎损伤之间不存在简单的相关性。此外，TREM2+/- 和 TREM2−/− 小鼠之间基因表达和小胶质细胞表型的差异表明，前者可以更好地模拟与 AD 风险相关的单拷贝 TREM2 变异。