Passive immunotherapies targeting Aβ continue to be evaluated as Alzheimer’s disease (AD) therapeutics, but there remains debate over the mechanisms by which these immunotherapies work. Besides the amount of preexisting Aβ deposition and the type of deposit (compact or diffuse), there is little data concerning what factors, independent of those intrinsic to the antibody, might influence efficacy. Here we (i) explored how constitutive priming of the underlying innate activation states by Il10 and Il6 might influence passive Aβ immunotherapy and (ii) evaluated transcriptomic data generated in the AMP-AD initiative to inform how these two cytokines and their receptors’ mRNA levels are altered in human AD and an APP mouse model. rAAV2/1 encoding EGFP, Il6 or Il10 were delivered by somatic brain transgenesis to neonatal (P0) TgCRND8 APP mice. Then, at 2 months of age, the mice were treated bi-weekly with a high-affinity anti-Aβ1–16 mAb5 monoclonal antibody or control mouse IgG until 6 months of age. rAAV mediated transgene expression, amyloid accumulation, Aβ levels and gliosis were assessed. Extensive transcriptomic data was used to evaluate the mRNA expression levels of IL10 and IL6 and their receptors in the postmortem human AD temporal cortex and in the brains of TgCRND8 mice, the later at multiple ages. Priming TgCRND8 mice with Il10 increases Aβ loads and blocks efficacy of subsequent mAb5 passive immunotherapy, whereas priming with Il6 priming reduces Aβ loads by itself and subsequent Aβ immunotherapy shows only a slightly additive effect. Transcriptomic data shows that (i) there are significant increases in the mRNA levels of Il6 and Il10 receptors in the TgCRND8 mouse model and temporal cortex of humans with AD and (ii) there is a great deal of variance in individual mouse brain and the human temporal cortex of these interleukins and their receptors. The underlying immune activation state can markedly affect the efficacy of passive Aβ immunotherapy. These results have important implications for ongoing human AD immunotherapy trials, as they indicate that underlying immune activation states within the brain, which may be highly variable, may influence the ability for passive immunotherapy to alter Aβ deposition.

中文翻译：

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调节先天免疫激活状态会影响特异性 Aβ 免疫疗法的功效

针对 Aβ 的被动免疫疗法继续被评估为阿尔茨海默病 (AD) 疗法，但对于这些免疫疗法的作用机制仍存在争议。除了预先存在的 Aβ 沉积量和沉积类型（紧凑型或扩散型）外，几乎没有关于哪些因素（独立于抗体固有因素）可能影响疗效的数据。在这里，我们 (i) 探讨了 Il10 和 Il6 对潜在先天激活状态的组成性启动如何影响被动 Aβ 免疫疗法，以及 (ii) 评估了 AMP-AD 计划中产生的转录组数据，以了解这两种细胞因子及其受体的 mRNA 水平如何在人类 AD 和 APP 小鼠模型中发生了改变。编码 EGFP、Il6 或 Il10 的 rAAV2/1 通过体细胞脑转基因传递给新生 (P0) TgCRND8 APP 小鼠。然后，在 2 个月大时，小鼠每两周接受一次高亲和力抗 Aβ1-16 mAb5 单克隆抗体或对照小鼠 IgG 治疗，直至 6 个月大。评估了 rAAV 介导的转基因表达、淀粉样蛋白积累、Aβ 水平和神经胶质增生。广泛的转录组数据用于评估死后人类 AD 颞叶皮层和 TgCRND8 小鼠大脑中 IL10 和 IL6 及其受体的 mRNA 表达水平，后者在多个年龄。用 Il10 引发 TgCRND8 小鼠会增加 Aβ 负荷并阻断后续 mAb5 被动免疫治疗的功效，而用 Il6 引发引发自身会降低 Aβ 负荷，随后的 Aβ 免疫治疗仅显示出轻微的累加效应。转录组学数据显示（i）TgCRND8 小鼠模型和 AD 人类颞叶皮层中 Il6 和 Il10 受体的 mRNA 水平显着增加，以及（ii）个体小鼠大脑和人类存在很大差异这些白介素及其受体的颞叶皮质。潜在的免疫激活状态会显着影响被动 Aβ 免疫疗法的疗效。这些结果对正在进行的人类 AD 免疫治疗试验具有重要意义，因为它们表明大脑内潜在的免疫激活状态可能高度可变，可能会影响被动免疫治疗改变 Aβ 沉积的能力。潜在的免疫激活状态会显着影响被动 Aβ 免疫疗法的疗效。这些结果对正在进行的人类 AD 免疫治疗试验具有重要意义，因为它们表明大脑内潜在的免疫激活状态可能高度可变，可能会影响被动免疫治疗改变 Aβ 沉积的能力。潜在的免疫激活状态会显着影响被动 Aβ 免疫疗法的疗效。这些结果对正在进行的人类 AD 免疫治疗试验具有重要意义，因为它们表明大脑内潜在的免疫激活状态可能高度可变，可能会影响被动免疫治疗改变 Aβ 沉积的能力。