Molecular Neuroplasticity, German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.
Institute of Inflammation and Neurodegeneration, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.
Glia. 2021 Jan;69(1):182-200. doi: 10.1002/glia.23894. Epub 2020 Aug 31.
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.
在阿尔茨海默病（AD）的晚期，小胶质细胞转变为激活表型，其突起变厚并回缩，迁移到淀粉样β（Aβ）斑块部位并增殖。在 AD 的早期阶段，小胶质细胞的功能是否改变以及哪些因素可能调节这些变化仍知之甚少。在这里，我们专注于研究 3-4 个月龄的 5xFAD 小鼠的后扣带回皮层（RSC）中的小胶质细胞，因为该小鼠是 AD 的转基因模型。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。然而，对神经 ECM 精细结构的组织化学评估显示，5xFAD 小鼠的神经周围网孔中 Wisteria floribunda 凝集素标记水平增加，并且 ECM 孔周围屏障的周长发生变化。双光子活体显微镜显示小胶质细胞的形态正常且静止运动，但 5xFAD 小鼠中迁移到光损伤部位的小胶质细胞数量明显减少。软骨素酶 ABC（ChABC）对 ECM 的酶消化可改善该缺陷。因此，通过流式细胞术对细胞表面标志物进行的表征显示小胶质细胞 CD45 的表达发生改变。此外，ChABC 处理可减少髓样来源的单核细胞向 5xFAD 小鼠 RSC 的浸润。因此，在淀粉样变性的早期阶段，小胶质细胞和髓样细胞的迁移都发生改变，并且至少部分通过 ECM 的衰减可以恢复。
