In the advanced stages of Alzheimer's disease (AD), microglia are transformed to an activated phenotype with thickened and retracted processes, migrate to the site of amyloid‐beta (Aβ) plaques, and proliferate. In the early stages of AD, it is still poorly understood whether the microglial function is altered and which factors may regulate these changes. Here, we focused on studying microglia in the retrosplenial cortex (RSC) in 3‐ to 4‐month‐old 5xFAD mice as a transgenic mouse model of AD. At this age, there are neither Aβ plaques, nor activation of microglia, nor dysregulation in the expression of genes encoding major extracellular matrix (ECM) molecules or extracellular proteases in the RSC. Still, histochemical evaluation of the fine structure of neural ECM revealed increased levels of Wisteria floribunda agglutinin labeling in holes of perineuronal nets and changes in the perimeter of ECM barriers around the holes in 5xFAD mice. Two‐photon vital microscopy demonstrated normal morphology and resting motility of microglia but strongly diminished number of microglial cells that migrated to the photolesion site in 5xFAD mice. Enzymatic digestion of ECM by chondroitinase ABC (ChABC) ameliorated this defect. Accordingly, the characterization of cell surface markers by flow cytometry demonstrated altered expression of microglial CD45. Moreover, ChABC treatment reduced the invasion of myeloid‐derived mononuclear cells into the RSC of 5xFAD mice. Hence, the migration of both microglia and myeloid cells is altered during the early stages of amyloidosis and can be restored at least partially by the attenuation of the ECM.

中文翻译：

---

细胞外基质的衰减可在淀粉样变性的早期恢复小胶质细胞的活性。

在阿尔茨海默病 (AD) 的晚期阶段，小胶质细胞转变为具有增厚和收缩过程的活化表型，迁移到淀粉样蛋白-β (Aβ) 斑块部位并增殖。在 AD 的早期阶段，对于小胶质细胞功能是否发生改变以及哪些因素可能调节这些变化仍然知之甚少。在这里，我们专注于研究 3 至 4 个月大的 5xFAD 小鼠的压后皮质 (RSC) 中的小胶质细胞，作为 AD 的转基因小鼠模型。在这个年龄，RSC 中既没有 Aβ 斑块，也没有小胶质细胞的激活，也没有编码主要细胞外基质 (ECM) 分子或细胞外蛋白酶的基因表达失调。尽管如此，神经 ECM 精细结构的组织化学评估显示紫藤的水平增加神经元周围网孔中的凝集素标记和 5xFAD 小鼠孔周围 ECM 屏障周长的变化。双光子生命显微镜显示小胶质细胞的形态和静息运动正常，但在 5xFAD 小鼠中迁移到光损伤部位的小胶质细胞数量大大减少。软骨素酶 ABC (ChABC) 对 ECM 的酶消化改善了这一缺陷。因此，通过流式细胞术对细胞表面标志物的表征证明了小胶质细胞 CD45 的表达改变。此外，ChABC 治疗减少了骨髓来源的单核细胞对 5xFAD 小鼠 RSC 的侵袭。因此，小胶质细胞和骨髓细胞的迁移在淀粉样变性的早期阶段都发生了改变，并且可以通过 ECM 的衰减至少部分恢复。