Department of Psychiatry and Behavioral Neurosciences, McMaster University, 1280 Main St. West, Hamilton, ON, L8S 4K1, Canada.
Department of Medicine, McMaster University, Hamilton, ON, Canada.
Alzheimers Res Ther. 2021 Jan 20;13(1):30. doi: 10.1186/s13195-020-00745-9.
Circulating autoantibodies and sex-dependent discrepancy in prevalence are unexplained phenomena of Alzheimer's disease (AD). Using the 3xTg-AD mouse model, we reported that adult males show early manifestations of systemic autoimmunity, increased emotional reactivity, enhanced expression of the histone variant macroH2A1 in the cerebral cortex, and loss of plaque/tangle pathology. Conversely, adult females display less severe autoimmunity and retain their AD-like phenotype. This study examines the link between immunity and other traits of the current 3xTg-AD model.
Young 3xTg-AD and wild-type mice drank a sucrose-laced 0.4 mg/ml solution of the immunosuppressant cyclophosphamide on weekends for 5 months. After behavioral phenotyping at 2 and 6 months of age, we assessed organ mass, serologic markers of autoimmunity, molecular markers of early AD pathology, and expression of genes associated with neurodegeneration.
Chronic immunosuppression prevented hematocrit drop and reduced soluble Aβ in 3xTg-AD males while normalizing the expression of histone variant macroH2A1 in 3xTg-AD females. This treatment also reduced hepatosplenomegaly, lowered autoantibody levels, and increased the effector T cell population while decreasing the proportion of regulatory T cells in both sexes. Exposure to cyclophosphamide, however, neither prevented reduced brain mass and BDNF expression nor normalized increased tau and anxiety-related behaviors.
The results suggest that systemic autoimmunity increases soluble Aβ production and affects transcriptional regulation of macroH2A1 in a sex-related manner. Despite the complexity of multisystem interactions, 3xTg-AD mice can be a useful in vivo model for exploring the regulatory role of autoimmunity in the etiology of AD-like neurodegenerative disorders.
循环自身抗体和患病率的性别差异是阿尔茨海默病（AD）的未解之谜。使用 3xTg-AD 小鼠模型，我们报告称成年雄性表现出全身自身免疫的早期表现、情绪反应增强、大脑皮层组蛋白变体 macroH2A1 的表达增强以及斑块/缠结病理的丧失。相反，成年雌性表现出较轻的自身免疫且保留其 AD 样表型。本研究探讨了当前 3xTg-AD 模型中免疫与其他特征之间的联系。
年轻的 3xTg-AD 和野生型小鼠在周末连续 5 个月饮用含免疫抑制剂环磷酰胺 0.4mg/ml 的蔗糖溶液。在 2 个月和 6 个月大时进行行为表型分析后，我们评估了器官质量、自身免疫的血清学标志物、早期 AD 病理的分子标志物以及与神经退行性变相关的基因表达。
慢性免疫抑制可防止 3xTg-AD 雄性的红细胞压积下降和可溶性 Aβ 增加，同时使 3xTg-AD 雌性的组蛋白变体 macroH2A1 表达正常化。这种治疗还减少了肝脾肿大、降低了自身抗体水平、增加了效应 T 细胞群体，同时减少了两性的调节性 T 细胞比例。然而，环磷酰胺的暴露既不能预防脑质量和 BDNF 表达的减少，也不能使增加的 tau 和焦虑相关行为正常化。
结果表明，全身自身免疫增加了可溶性 Aβ 的产生，并以性别相关的方式影响 macroH2A1 的转录调控。尽管存在多系统相互作用的复杂性，但 3xTg-AD 小鼠可以作为探索自身免疫在 AD 样神经退行性疾病发病机制中的调节作用的有用体内模型。
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