Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
Central Laboratories for Key Technologies, Kirin Company Ltd, Yokohama-shi, Kanagawa, Japan.
Curr Alzheimer Res. 2020;17(1):52-59. doi: 10.2174/1567205017666200212160343.
Alzheimer's disease (AD) is a neurodegenerative disorder histopathologically characterized by the accumulation of amyloid β (Aβ) peptides and inflammation associated with activated microglia. These features are well investigated in the central nervous system using AD-model mice; however, peripheral inflammation in these mice has not been investigated well.
We evaluated the inflammatory responses, especially myeloid dendritic cells (mDCs), in peripheral lymphoid tissues in AD-model mice to determine their association with Aβ deposition.
We collected lymphocytes from mesenteric lymphoid nodes (MLNs) and Peyer's patches (PPs) of 5×FAD transgenic mice used as an AD model. Lymphocytes were analyzed using a flow cytometer to characterize mDCs and T cells. Collected lymphocytes were treated with Aβ1-42 ex vivo to evaluate the inflammatory response.
We observed elevated levels of inflammatory cytokines and chemokines including interleukin (IL)-12 and macrophage inflammatory protein-1α in mDCs from MLNs and PPs and reduced levels of programmed death-ligand-1, an immunosuppressive co-stimulatory molecule, on the surface of mDCs from 5×FAD mice. Additionally, we found increases in interferon (IFN)-γ-producing CD4- or CD8- positive T cells in MLNs were increased in 5×FAD mice. Moreover, ex vivo treatment with Aβ peptides increased the production of IL-12 and IFN-γ by lymphocytes from 5×FAD mice.
The present study showed that pro-inflammatory mDC and T cells were induced in MLNs and PPs of 5×FAD mice.
阿尔茨海默病（AD）是一种神经退行性疾病，组织病理学上的特征是淀粉样β（Aβ）肽的积累和与活化的小胶质细胞相关的炎症。这些特征在 AD 模型小鼠的中枢神经系统中得到了很好的研究；然而，这些小鼠的外周炎症尚未得到很好的研究。
我们评估了 AD 模型小鼠外周淋巴组织中的炎症反应，特别是髓样树突状细胞（mDC），以确定其与 Aβ沉积的关系。
我们从 5×FAD 转基因小鼠（用作 AD 模型）的肠系膜淋巴结（MLN）和派尔氏斑（PP）中收集淋巴细胞。使用流式细胞仪分析淋巴细胞，以表征 mDC 和 T 细胞。收集的淋巴细胞进行 Aβ1-42 体外处理，以评估炎症反应。
我们观察到 MLN 和 PP 中的 mDC 中炎症细胞因子和趋化因子水平升高，包括白细胞介素（IL）-12 和巨噬细胞炎症蛋白-1α，以及 mDC 表面程序性死亡配体-1（一种免疫抑制共刺激分子）水平降低，在 5×FAD 小鼠中。此外，我们发现 5×FAD 小鼠 MLN 中 IFN-γ 产生的 CD4 或 CD8 阳性 T 细胞增加。此外，Aβ 肽的体外处理增加了来自 5×FAD 小鼠的淋巴细胞产生 IL-12 和 IFN-γ 的能力。
本研究表明，促炎 mDC 和 T 细胞在 5×FAD 小鼠的 MLN 和 PP 中被诱导。
