PDF(Pubmed)
Abstract：
The term neuroinflammation defines the reactions of astrocytes and microglia to alterations in homeostasis in the diseased central nervous system (CNS), the exacerbation of which contributes to the neurodegenerative effects of Alzheimer\'s disease (AD). Local environmental conditions, such as the presence of proinflammatory molecules, mechanical properties of the extracellular matrix (ECM), and local cell-cell interactions, are determinants of glial cell phenotypes. In AD, the load of the cytotoxic/proinflammatory amyloid β (Aβ) peptide is a microenvironmental component increasingly growing in the CNS, imposing time-evolving challenges on resident cells. This study aimed to investigate the temporal and spatial variations of the effects produced by this process on astrocytes and microglia, either directly or by interfering in their interactions. Ex vivo confocal analyses of hippocampal sections from the mouse model TgCRND8 at different ages have shown that overproduction of Aβ peptide induced early and time-persistent disassembly of functional astroglial syncytium and promoted a senile phenotype of reactive microglia, hindering Aβ clearance. In the late stages of the disease, these patterns were altered in the presence of Aβ-plaques, surrounded by typically reactive astrocytes and microglia. Morphofunctional characterization of peri-plaque gliosis revealed a direct contribution of astrocytes in plaque buildup that might result in shielding Aβ-peptide cytotoxicity and, as a side effect, in exacerbating neuroinflammation.
摘要：
术语神经炎症定义了星形胶质细胞和小胶质细胞对患病中枢神经系统（CNS）稳态改变的反应。其恶化有助于阿尔茨海默病（AD）的神经退行性作用。当地环境条件,比如促炎分子的存在，细胞外基质（ECM）的机械性能，和局部细胞间的相互作用，是神经胶质细胞表型的决定因素。在AD中,细胞毒性/促炎性淀粉样β（Aβ）肽的负荷是中枢神经系统中越来越多的微环境成分，对常驻细胞施加随时间变化的挑战。本研究旨在研究该过程对星形胶质细胞和小胶质细胞产生的影响的时空变化。直接或通过干扰它们的相互作用。不同年龄小鼠模型TgCRND8海马切片的离体共聚焦分析表明，Aβ肽的过量产生诱导功能性星形胶质细胞合胞体的早期和持续分解，并促进反应性小胶质细胞的衰老表型，阻碍Aβ清除。在疾病的晚期，这些模式在Aβ斑块的存在下发生了改变，被典型的反应性星形胶质细胞和小胶质细胞包围。斑块周围胶质细胞增生的形态功能表征揭示了星形胶质细胞在斑块积聚中的直接贡献，这可能导致屏蔽Aβ肽的细胞毒性，作为副作用，加剧神经炎症。
