Immune and Inflammatory Determinants Underlying Alzheimer's Disease Pathology
Immune and Inflammatory Determinants Underlying Alzheimer's Disease Pathology
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DOI：
10.1007/s11481-020-09908-9
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发表时间：
2020-02-24
影响因子：
6.2
通讯作者：
Agrawal, Anshu
中科院分区：
文献类型：
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作者：
Baulch, Janet E.;Acharya, Munjal M.;Agrawal, Anshu
本研究探讨了在阿尔茨海默病（AD）神经病理学和认知缺陷的延续中外周免疫变化之间的联系。我们使用人类AD患者和啮齿动物模型的研究设计得到了过去基因组研究证据的支持。我们观察到，与健康对照相比，AD和轻度认知障碍患者的血清中A β特异性IgG抗体增加，表明对A β有积极的免疫反应。在5xFAD小鼠AD模型中也证实了类似的IgG升高和抗A β的IgM抗体降低。更重要的是，我们观察到IgM水平降低与表现为记忆巩固受损的认知功能障碍之间的负相关。与野生型对照相比，AD小鼠大脑小胶质细胞和脾脏巨噬细胞的激活增加，支持了强外周免疫激活。此外，参与抗体类别转换的炎症细胞因子IL-21在AD患者血浆中升高，并与IgG抗体水平呈正相关。同时，在AD小鼠脾细胞中观察到IL-21和IL-17的升高。进一步研究发现，AD小鼠脾脏中分泌IL-21的T滤泡辅助细胞（Tfh）的比例增加。与Tfh相反，在AD小鼠中B1细胞产生IgM抗体的频率降低。总之，这些数据表明，在AD中，对A β的免疫耐受受到损害，导致对A β的慢性免疫/炎症反应，这是有害的，并导致神经病理。
This study examines the link between peripheral immune changes in perpetuation of the Alzheimer's disease (AD) neuropathology and cognitive deficits. Our research design using human AD patients and rodent model is supported by past evidence from genomic studies. We observed an active immune response against A beta as indicated by the increased A beta specific IgG antibody in the serum of AD and patients with mild cognitive impairments as compared to healthy controls. A similar increase in IgG and decrease in IgM antibody against A beta was also confirmed in the 5xFAD mouse model of AD. More importantly, we observed a negative correlation between reduced IgM levels and cognitive dysfunction that manifested as impaired memory consolidation. Strong peripheral immune activation was supported by increased activation of microglia in the brain and macrophages in the spleen of AD mice compared to wild type control littermates. Furthermore, inflammatory cytokine IL-21 that is involved in antibody class switching was elevated in the plasma of AD patients and correlated positively with the IgG antibody levels. Concurrently, an increase in IL-21 and IL-17 was observed in spleen cells from AD mice. Further investigation revealed that proportions of T follicular helper (Tfh) cells that secrete IL-21 are increased in the spleen of AD mice. In contrast to Tfh, the frequency of B1 cells that produce IgM antibodies was reduced in AD mice. Altogether, these data indicate that in AD the immune tolerance to A beta is compromised leading to chronic immune/inflammatory responses against A beta that are detrimental and cause neuropathology.