Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, 3600 Spruce St, Philadelphia, PA, 19104, USA.
Neurosience, Janssen Research & Development, Janssen Pharmaceutica NV (Division of Johnson & Johnson), Turnhoutseweg 30, 2340, Beerse, Belgium.
Acta Neuropathol Commun. 2021 Sep 9;9(1):150. doi: 10.1186/s40478-021-01251-1.
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.
在阿尔茨海默病（AD）大脑中，与 Aβ 斑块相关的神经元过程中存在神经原纤维缠结（NP）tau 病理学。小胶质细胞也与这些斑块接近，并且小胶质细胞基因变体是 AD 的已知风险因素，包括 TREM2 的功能丧失变体。我们进一步研究了在脑内注射 AD 脑源性病理 tau（AD-tau）后形成 NP tau 病理学的 5XFAD 小鼠中，与 Aβ 斑块相关的小胶质细胞的作用，重点研究了在用集落刺激因子 1（CSFR1）抑制剂 PLX3397 治疗后 TREM2 表达减少和小胶质细胞耗竭的后果。用 PLX3397 治疗的年轻 5XFAD 小鼠大脑中的小胶质细胞大量减少，包括皮质斑块相关的小胶质细胞，皮质中的 Aβ 斑块负担显著减少。在用 PLX3397 治疗的 5XFAD 小鼠中，脑内注射 AD-tau 后，观察到皮质 APP 阳性的神经原纤维缠结和 NP tau 病理学的相应减少。与之前的报告一致，5XFAD×TREM2 小鼠的斑块相关小胶质细胞显著减少，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，注射 AD-tau 的 5XFAD×TREM2 小鼠的 AT8 阳性 NP tau 相对 5XFAD×TREM2 小鼠大大增加。表达谱分析显示，5XFAD×TREM2 小鼠的大脑中存在与疾病相关的小胶质细胞（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，脑内 AD-tau 注射的 5XFAD×TREM2 和 5XFAD×TREM2 小鼠之间的皮质和海马基因表达存在显著差异，包括与小胶质细胞功能相关的途径。这些数据表明，小胶质细胞与斑块相互作用的程度与斑块相关的神经原纤维缠结损伤之间没有简单的相关性。此外，TREM2 和 TREM2 小鼠之间的基因表达和小胶质细胞表型差异表明，前者可能更好地模拟与 AD 风险相关的单个拷贝 TREM2 变体。
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