Genetic and pathologic data suggest that amyloid beta (Aβ), produced by processing of the amyloid precursor protein, is a major initiator of Alzheimer's disease (AD). To gain new insights into Aβ modulation, we sought to harness the power of the coevolution between the neurotropic parasite Toxoplasma gondii and the mammalian brain. Two prior studies attributed Toxoplasma-associated protection against Aβ to increases in anti-inflammatory cytokines (TGF-β and IL-10) and infiltrating phagocytic monocytes. These studies only used one Toxoplasma strain making it difficult to determine if the noted changes were associated with Aβ protection or simply infection. To address this limitation, we infected a third human amyloid precursor protein AD mouse model (J20) with each of the genetically distinct, canonical strains of Toxoplasma (Type I, Type II, or Type III). We then evaluated the central nervous system (CNS) for Aβ deposition, immune cell responses, global cytokine environment, and parasite burden. We found that only Type II infection was protective against Aβ deposition despite both Type II and Type III strains establishing a chronic CNS infection and inflammatory response. Compared with uninfected and Type I-infected mice, both Type II- and Type III-infected mice showed increased numbers of CNS T cells and microglia and elevated pro-inflammatory cytokines, but neither group showed a >2-fold elevation of TGF-β or IL-10. These data suggest that we can now use our identification of protective (Type II) and nonprotective (Type III) Toxoplasma strains to determine what parasite and host factors are linked to decreased Aβ burden rather than simply with infection.

中文翻译：

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使用嗜神经寄生虫弓形虫的不同菌株作为新工具来剖析淀粉样蛋白沉积。


遗传和病理数据表明，淀粉样蛋白前体蛋白加工产生的β淀粉样蛋白（Aβ）是阿尔茨海默病（AD）的主要引发因素。为了获得对 Aβ 调节的新见解，我们试图利用嗜神经寄生虫弓形虫和哺乳动物大脑之间共同进化的力量。先前的两项研究将弓形虫相关的 Aβ 保护作用归因于抗炎细胞因子（TGF-β 和 IL-10）和浸润吞噬单核细胞的增加。这些研究仅使用了一种弓形虫菌株，因此很难确定所注意到的变化是否与 Aβ 保护相关或仅仅是感染相关。为了解决这一限制，我们用每种遗传上不同的典型弓形虫菌株（I 型、II 型或 III 型）感染了第三个人类淀粉样蛋白前体蛋白 AD 小鼠模型 (J20)。然后，我们评估了中枢神经系统 (CNS) 的 Aβ 沉积、免疫细胞反应、整体细胞因子环境和寄生虫负荷。我们发现，尽管 II 型和 III 型菌株都建立了慢性 CNS 感染和炎症反应，但只有 II 型感染能够防止 Aβ 沉积。与未感染和I型感染的小鼠相比，II型和III型感染的小鼠均表现出中枢神经系统T细胞和小胶质细胞数量增加以及促炎细胞因子升高，但两组均未表现出TGF-β升高>2倍或IL-10。这些数据表明，我们现在可以利用对保护性（II 型）和非保护性（III 型）弓形虫菌株的鉴定来确定哪些寄生虫和宿主因素与 Aβ 负荷减少有关，而不仅仅是与感染有关。