Division of Psychiatry Research, University of Zurich, Wagistrasse 12, 8952, Schlieren, Switzerland.
Neuroscience Center Zurich (ZNZ), Wintherthurerstrasse 190, 8057, Zurich, Switzerland.
Acta Neuropathol Commun. 2015 Nov 11;3:71. doi: 10.1186/s40478-015-0251-x.
In Alzheimer's disease, accumulation and pathological aggregation of amyloid β-peptide is accompanied by the induction of complex immune responses, which have been attributed both beneficial and detrimental properties. Such responses implicate various cell types of the innate and adaptive arm of the immunesystem, both inside the central nervous system, and in the periphery. To investigate the role of the adaptive immune system in brain β-amyloidosis, PSAPP transgenic mice, an established mouse model of Alzheimer's disease, were crossbred with the recombination activating gene-2 knockout (Rag2 ko) mice lacking functional B and T cells. In a second experimental paradigm, aged PSAPP mice were reconstituted with bone marrow cells from either Rag2 ko or wildtype control mice.
Analyses from both experimental approaches revealed reduced β-amyloid pathology and decreased brain amyloid β-peptide levels in PSAPP mice lacking functional adaptive immune cells. The decrease in brain β-amyloid pathology was associated with enhanced microgliosis and increased phagocytosis of amyloid β-peptide aggregates.
The results of this study demonstrate an impact of the adaptive immunity on cerebral β-amyloid pathology in vivo and suggest an influence on microglia-mediated amyloid β-peptide clearance as a possible underlying mechanism.
在阿尔茨海默病中，淀粉样 β-肽的积累和病理性聚集伴随着复杂的免疫反应的诱导，这些反应既有有益的也有有害的特性。这些反应涉及到免疫系统的先天和适应性免疫臂的各种细胞类型，包括中枢神经系统内和外周的细胞。为了研究适应性免疫系统在脑 β-淀粉样蛋白中的作用，PSAPP 转基因小鼠，一种已建立的阿尔茨海默病小鼠模型，与缺乏功能性 B 和 T 细胞的重组激活基因-2 敲除 (Rag2 ko) 小鼠进行了杂交。在第二个实验范例中，用来自 Rag2 ko 或野生型对照小鼠的骨髓细胞对老年 PSAPP 小鼠进行了重建。
来自两种实验方法的分析表明，缺乏功能性适应性免疫细胞的 PSAPP 小鼠的 β-淀粉样蛋白病理减少，脑内淀粉样 β-肽水平降低。脑 β-淀粉样蛋白病理的减少与小胶质细胞增生增强和淀粉样 β-肽聚集物的吞噬作用增加有关。
这项研究的结果表明适应性免疫对体内脑 β-淀粉样蛋白病理有影响，并表明对小胶质细胞介导的淀粉样 β-肽清除的影响可能是其潜在机制。
