Department of Biomedical Sciences, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, Florida, USA.
Department of Neuroscience, Marcus Neuroscience Institute, Boca Raton Medical Center, Boca Raton, Florida, USA.
J Cell Physiol. 2024 Jun;239(6):e30916. doi: 10.1002/jcp.30916. Epub 2022 Nov 21.
The role of Aβ plaques and neurofibrillary tangles in Alzheimer's disease (AD) pathogenesis have recently come into question due to failure of many pharmaceutical agents targeting these deposits and detection of these misfolded proteins in normal human brains. Therefore, we investigated correlations between microglial activation and toll like receptor 4 (TLR4) and Lck/Yes novel tyrosine (LYN) kinase signaling in an AD mouse model. In this study, we used 5-6-month-old 5XFAD and wild type (WT) male and female mice. Immunohistochemistry (IHC) and flow cytometry (FC) were performed on their brains. Cognitive performance was assessed with the Barnes-Maze. IHC showed more Ab aggregation in microglia of female 5XFAD mice compared to their male counterparts. Increased co-localization of microglial TLR4 and LYN was also observed in AD more than WT and females more than males. IHC also suggests microglial phagocytosis of neurons in AD mice, which is supported by FC data. Our FC data also support the involvement of disease associated microglia (DAMs) in this process based on cytokine secretion. Cognitive assessment by the Barnes maze showed 5XFAD females performed worse than males. In this study, we investigated the relationship between microglial TLR4 and LYN kinase in 5XFAD male and females. Our data reveals a correlation between microglial TLR4 and LYN co-localization and AD pathogenesis, more in females than males. Targeting microglial TLR4 and Lyn in DAMs may offer new therapeutic opportunities in the treatment of AD.
淀粉样蛋白斑块和神经原纤维缠结在阿尔茨海默病（AD）发病机制中的作用最近受到质疑，因为许多针对这些沉积物的药物都失败了，而且在正常人类大脑中也检测到了这些错误折叠的蛋白质。因此，我们研究了 AD 小鼠模型中微胶质细胞激活与 Toll 样受体 4（TLR4）和 Lck/Yes 新型酪氨酸（LYN）激酶信号之间的相关性。在这项研究中，我们使用了 5-6 个月大的 5XFAD 和野生型（WT）雄性和雌性小鼠。对它们的大脑进行了免疫组织化学（IHC）和流式细胞术（FC）检测。使用 Barnes 迷宫评估认知表现。IHC 显示 5XFAD 雌性小鼠的微胶质细胞中 Ab 聚集更多。还观察到 AD 中微胶质 TLR4 和 LYN 的共定位增加，WT 和雌性比雄性更明显。IHC 还表明 AD 小鼠的小胶质细胞吞噬神经元，FC 数据也支持这一点。我们的 FC 数据还支持疾病相关小胶质细胞（DAMs）在该过程中的参与，这是基于细胞因子的分泌。通过 Barnes 迷宫进行的认知评估显示 5XFAD 雌性的表现比雄性差。在这项研究中，我们研究了 5XFAD 雄性和雌性中微胶质 TLR4 和 LYN 激酶之间的关系。我们的数据表明，微胶质 TLR4 和 LYN 共定位与 AD 发病机制之间存在相关性，在雌性中比雄性更明显。针对 DAMs 中的微胶质 TLR4 和 Lyn 可能为 AD 的治疗提供新的治疗机会。
