The misfolding of host-encoded proteins into pathological prion conformations is a defining characteristic of many neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, and Lewy body dementia. A current area of intense study is the way in which the pathological deposition of these proteins might influence each other, as various combinations of co-pathology between prion-capable proteins are associated with exacerbation of disease. A spectrum of pathological, genetic and biochemical evidence provides credence to the notion that amyloid β (Aβ) accumulation can induce and promote α-synuclein pathology, driving neurodegeneration. To assess the interplay between α-synuclein and Aβ on protein aggregation kinetics, we crossed mice expressing human α-synuclein (M20) with APPswe/PS1dE9 transgenic mice (L85) to generate M20/L85 mice. We then injected α-synuclein preformed fibrils (PFFs) unilaterally into the hippocampus of 6-month-old mice, harvesting 2 or 4 months later. Immunohistochemical analysis of M20/L85 mice revealed that pre-existing Aβ plaques exacerbate the spread and deposition of induced α-synuclein pathology. This process was associated with increased neuroinflammation. Unexpectedly, the injection of α-synuclein PFFs in L85 mice enhanced the deposition of Aβ; whereas the level of Aβ deposition in M20/L85 bigenic mice, injected with α-synuclein PFFs, did not differ from that of mice injected with PBS. These studies reveal novel and unexpected interplays between α-synuclein pathology, Aβ and neuroinflammation in mice that recapitulate the pathology of Alzheimer’s disease and Lewy body dementia.

中文翻译：

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α-突触核蛋白和 Aβ 的共谋加重了新型朊病毒型小鼠模型的并发症


宿主编码的蛋白质错误折叠成病理性朊病毒构象是许多神经退行性疾病的一个决定性特征，包括阿尔茨海默病、帕金森病和路易体痴呆。当前深入研究的一个领域是这些蛋白质的病理沉积可能相互影响的方式，因为具有朊病毒的蛋白质之间的共同病理学的各种组合与疾病的恶化有关。一系列病理、遗传和生化证据证实了 β 淀粉样蛋白 (Aβ) 积累可以诱导和促进 α-突触核蛋白病理学，从而驱动神经退行性变的观点。为了评估 α-突触核蛋白和 Aβ 对蛋白质聚集动力学的相互作用，我们将表达人 α-突触核蛋白 (M20) 的小鼠与 APPswe/PS1dE9 转基因小鼠 (L85) 杂交，产生 M20/L85 小鼠。然后，我们将 α-突触核蛋白预制原纤维 (PFF) 单侧注射到 6 个月大小鼠的海马体中，并在 2 或 4 个月后收获。 M20/L85 小鼠的免疫组织化学分析表明，预先存在的 Aβ 斑块加剧了诱导的 α-突触核蛋白病理学的扩散和沉积。这个过程与神经炎症的增加有关。出乎意料的是，在L85小鼠体内注射α-突触核蛋白PFFs增强了Aβ的沉积；而注射 α-突触核蛋白 PFF 的 M20/L85 双基因小鼠中 Aβ 沉积水平与注射 PBS 的小鼠没有差异。这些研究揭示了小鼠体内 α-突触核蛋白病理学、Aβ 和神经炎症之间新颖且意想不到的相互作用，概括了阿尔茨海默病和路易体痴呆的病理学。