MacPherson Kathryn P, Sompol Pradoldej, Kannarkat George T, Chang Jianjun, Sniffen Lindsey, Wildner Mary E, Norris Christopher M, Tansey Malú G
Emory University School of Medicine, 30322, United States.
Sanders-Brown Center on Aging, University of Kentucky College of Medicine, Lexington, KY 40536, United States.
Neurobiol Dis. 2017 Jun;102:81-95. doi: 10.1016/j.nbd.2017.02.010. Epub 2017 Feb 24.
Clinical and animal model studies have implicated inflammation and peripheral immune cell responses in the pathophysiology of Alzheimer's disease (AD). Peripheral immune cells including T cells circulate in the cerebrospinal fluid (CSF) of healthy adults and are found in the brains of AD patients and AD rodent models. Blocking entry of peripheral macrophages into the CNS was reported to increase amyloid burden in an AD mouse model. To assess inflammation in the 5xFAD (Tg) mouse model, we first quantified central and immune cell profiles in the deep cervical lymph nodes and spleen. In the brains of Tg mice, activated (MHCII, CD45, and Ly6C) myeloid-derived CD11b immune cells are decreased while CD3 T cells are increased as a function of age relative to non-Tg mice. These immunological changes along with evidence of increased mRNA levels for several cytokines suggest that immune regulation and trafficking patterns are altered in Tg mice. Levels of soluble Tumor Necrosis Factor (sTNF) modulate blood-brain barrier (BBB) permeability and are increased in CSF and brain parenchyma post-mortem in AD subjects and Tg mice. We report here that in vivo peripheral administration of XPro1595, a novel biologic that sequesters sTNF into inactive heterotrimers, reduced the age-dependent increase in activated immune cells in Tg mice, while decreasing the overall number of CD4 T cells. In addition, XPro1595 treatment in vivo rescued impaired long-term potentiation (LTP) measured in brain slices in association with decreased Aβ plaques in the subiculum. Selective targeting of sTNF may modulate brain immune cell infiltration, and prevent or delay neuronal dysfunction in AD.
Immune cells and cytokines perform specialized functions inside and outside the brain to maintain optimal brain health; but the extent to which their activities change in response to neuronal dysfunction and degeneration is not well understood. Our findings indicate that neutralization of sTNF reduced the age-dependent increase in activated immune cells in Tg mice, while decreasing the overall number of CD4 T cells. In addition, impaired long-term potentiation (LTP) was rescued by XPro1595 in association with decreased hippocampal Aβ plaques. Selective targeting of sTNF holds translational potential to modulate brain immune cell infiltration, dampen neuroinflammation, and prevent or delay neuronal dysfunction in AD.
临床和动物模型研究表明炎症和外周免疫细胞反应与阿尔茨海默病（AD）的病理生理学有关。包括T细胞在内的外周免疫细胞在健康成年人的脑脊液（CSF）中循环，并在AD患者和AD啮齿动物模型的大脑中被发现。据报道，在AD小鼠模型中，阻断外周巨噬细胞进入中枢神经系统会增加淀粉样蛋白负担。为了评估5xFAD（Tg）小鼠模型中的炎症，我们首先对颈深淋巴结和脾脏中的中枢和免疫细胞谱进行了定量分析。在Tg小鼠的大脑中，随着年龄增长，与非Tg小鼠相比，活化的（MHCII、CD45和Ly6C）骨髓来源的CD11b免疫细胞减少，而CD3 T细胞增加。这些免疫变化以及几种细胞因子mRNA水平升高的证据表明，Tg小鼠的免疫调节和运输模式发生了改变。可溶性肿瘤坏死因子（sTNF）水平调节血脑屏障（BBB）通透性，在AD患者和Tg小鼠死后的脑脊液和脑实质中升高。我们在此报告，在体内外周给予XPro1595（一种将sTNF螯合为无活性异源三聚体的新型生物制剂）可减少Tg小鼠中活化免疫细胞随年龄增长的增加，同时减少CD4 T细胞的总数。此外，体内XPro1595治疗挽救了在脑片中测量的受损长时程增强（LTP），并伴有下托中Aβ斑块减少。选择性靶向sTNF可能调节脑免疫细胞浸润，并预防或延缓AD中的神经元功能障碍。
免疫细胞和细胞因子在脑内外发挥特殊功能以维持最佳脑健康；但其活动因神经元功能障碍和退化而改变的程度尚不清楚。我们的研究结果表明，中和sTNF可减少Tg小鼠中活化免疫细胞随年龄增长的增加，同时减少CD4 T细胞的总数。此外，XPro1595挽救了受损的长时程增强（LTP），并伴有海马Aβ斑块减少。选择性靶向sTNF具有调节脑免疫细胞浸润、减轻神经炎症以及预防或延缓AD中神经元功能障碍的转化潜力。
