Molecular Pharmacology and Physiology, College of Medicine, University of South Florida, Tampa, FL, United States.
Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, United States.
Front Immunol. 2020 May 20;11:997. doi: 10.3389/fimmu.2020.00997. eCollection 2020.
Innate immune activation is a major contributor to Alzheimer's Disease (AD) pathophysiology, although the mechanisms involved are poorly understood. Chemokine C-C motif ligand (CCL) 2 is produced by neurons and glial cells and is upregulated in the AD brain. Transgene expression of CCL2 in mouse models of amyloidosis produces microglia-induced amyloid β oligomerization, a strong indication of the role of these activation pathways in the amyloidogenic processes of AD. We have previously shown that CCL2 polarizes microglia in wild type mice. However, how CCL2 signaling contributes to tau pathogenesis remains unknown. To address this question, CCL2 was delivered via recombinant adeno-associated virus serotype 9 into both cortex and hippocampus of a mouse model with tau pathology (rTg4510). We report that CCL2 overexpression aggravated tau pathology in rTg4510 as shown by the increase in Gallyas stained neurofibrillary tangles as well as phosphorylated tau-positive inclusions. In addition, biochemical analysis showed a reduction in the levels of detergent-soluble tau species followed by increase in the insoluble fraction, indicating a shift toward larger tau aggregates. Indeed, increased levels of high molecular weight species of phosphorylated tau were found in the mice injected with CCL2. We also report that worsening of tau pathology following CCL2 overexpression was accompanied by a distinct inflammatory response. We report an increase in leukocyte common antigen (CD45) and Cluster of differentiation 68 (CD68) expression in the brain of rTg4510 mice without altering the expression levels of a cell-surface protein Transmembrane Protein 119 (Tmem119) and ionized calcium-binding adaptor molecule 1 (Iba-1) in resident microglia. Furthermore, the analysis of cytokines in brain extract showed a significant increase in interleukin (IL)-6 and CCL3, while CCL5 levels were decreased in CCL2 mice. No changes were observed in IL-1α, IL-1β, TNF-α. IL-4, Vascular endothelial growth factor-VEGF, IL-13 and CCL11. Taken together our data report for the first time that overexpression of CCL2 promotes the increase of pathogenic tau species and is associated with glial neuroinflammatory changes that are deleterious. We propose that these events may contribute to the pathogenesis of Alzheimer's disease and other tauopathies.
先天免疫激活是阿尔茨海默病 (AD) 病理生理学的主要贡献者，尽管涉及的机制尚不清楚。趋化因子 C-C 基序配体 (CCL) 2 由神经元和神经胶质细胞产生，并在 AD 大脑中上调。淀粉样蛋白病小鼠模型中转基因表达 CCL2 会导致小胶质细胞诱导的淀粉样 β 寡聚化，这强烈表明这些激活途径在 AD 的淀粉样蛋白形成过程中起作用。我们之前已经表明，CCL2 使野生型小鼠中的小胶质细胞极化。然而，CCL2 信号如何导致 tau 发病机制尚不清楚。为了解决这个问题，我们通过重组腺相关病毒血清型 9 将 CCL2 递送至具有 tau 病理学的小鼠模型 (rTg4510) 的皮质和海马体中。我们报告说，CCL2 过表达加剧了 rTg4510 中的 tau 病理学，表现为 Gallyas 染色神经原纤维缠结以及磷酸化 tau 阳性包涵体的增加。此外，生化分析显示去污剂可溶性 tau 物种的水平降低，随后不溶性部分增加，表明向更大的 tau 聚集体转移。事实上，在注射 CCL2 的小鼠中发现了高水平的磷酸化 tau 高分子量物种。我们还报告说，CCL2 过表达后 tau 病理学的恶化伴随着明显的炎症反应。我们报告说，在 rTg4510 小鼠的大脑中，白细胞共同抗原 (CD45) 和分化簇 68 (CD68) 的表达增加，而在驻留小胶质细胞中不变细胞表面蛋白跨膜蛋白 119 (Tmem119) 和离子钙结合接头分子 1 (Iba-1) 的表达水平。此外，脑提取物中细胞因子的分析显示白细胞介素 (IL)-6 和 CCL3 显著增加，而 CCL2 小鼠中的 CCL5 水平降低。在 CCL2 小鼠中未观察到 IL-1α、IL-1β、TNF-α、IL-4、血管内皮生长因子-VEGF、IL-13 和 CCL11 的变化。总之，我们的数据首次报告，CCL2 的过表达促进了致病性 tau 物种的增加，并与神经胶质神经炎症变化有关，这些变化是有害的。我们提出，这些事件可能有助于阿尔茨海默病和其他 tau 病的发病机制。
