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 Aβ as indicated by the increased Aβ 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 Aβ 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 Aβ is compromised leading to chronic immune/inflammatory responses against Aβ that are detrimental and cause neuropathology.

这项研究检查了阿尔茨海默病 (AD) 神经病理学持续存在的外周免疫变化与认知缺陷之间的联系。我们使用人类 AD 患者和啮齿动物模型的研究设计得到了基因组研究过去证据的支持。我们观察到针对 Aβ 的主动免疫反应，如与健康对照相比，AD 和轻度认知障碍患者血清中 Aβ 特异性 IgG 抗体增加所表明的。在 AD 的 5xFAD 小鼠模型中也证实了针对 Aβ 的 IgG 的类似增加和 IgM 抗体的减少。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呈负相关。与野生型对照同窝仔鼠相比，AD 小鼠大脑中小胶质细胞和脾脏中巨噬细胞的激活增加，支持了强烈的外周免疫激活。此外，参与抗体类别转换的炎性细胞因子 IL-21 在 AD 患者的血浆中升高，并与 IgG 抗体水平呈正相关。同时，在来自 AD 小鼠的脾细胞中观察到 IL-21 和 IL-17 的增加。进一步的研究表明，AD 小鼠脾脏中分泌 IL-21 的 T 滤泡辅助 (Tfh) 细胞的比例增加。与 Tfh 相比，AD 小鼠中 B1 细胞产生 IgM 抗体的频率降低。共，