Fraunhofer Institute of Cell Therapy and Immunology, Department of Drug Design and Target Validation IZI-MWT, 06120 Halle, Germany.
Fraunhofer Institute of Cell Therapy and Immunology IZI, 04103 Leipzig, Germany.
Molecules. 2020 Jan 29;25(3):580. doi: 10.3390/molecules25030580.
Alzheimer's disease (AD) and Parkinson's disease (PD), including dementia with Lewy bodies (DLB), account for the majority of dementia cases worldwide. Interestingly, a significant number of patients have clinical and neuropathological features of both AD and PD, i.e., the presence of amyloid deposits and Lewy bodies in the neocortex. The identification of α-synuclein peptides in amyloid plaques in DLB brain led to the hypothesis that both peptides mutually interact with each other to facilitate neurodegeneration. In this article, we report the influence of Aβ(1-42) and pGlu-Aβ(3-42) on the aggregation of α-synuclein in vitro. The aggregation of human recombinant α-synuclein was investigated using thioflavin-T fluorescence assay. Fibrils were investigated by means of antibody conjugated immunogold followed by transmission electron microscopy (TEM). Our data demonstrate a significantly increased aggregation propensity of α-synuclein in the presence of minor concentrations of Aβ(1-42) and pGlu-Aβ(3-42) for the first time, but without effect on toxicity on mouse primary neurons. The analysis of the composition of the fibrils by TEM combined with immunogold labeling of the peptides revealed an interaction of α-synuclein and Aβ in vitro, leading to an accelerated fibril formation. The analysis of kinetic data suggests that significantly enhanced nucleus formation accounts for this effect. Additionally, co-occurrence of α-synuclein and Aβ and pGlu-Aβ, respectively, under pathological conditions was confirmed in vivo by double immunofluorescent labelings in brains of aged transgenic mice with amyloid pathology. These observations imply a cross-talk of the amyloid peptides α-synuclein and Aβ species in neurodegeneration. Such effects might be responsible for the co-occurrence of Lewy bodies and plaques in many dementia cases.
阿尔茨海默病（AD）和帕金森病（PD），包括路易体痴呆（DLB），占全球痴呆症病例的大多数。有趣的是，相当数量的患者具有 AD 和 PD 的临床和神经病理学特征，即新皮层中存在淀粉样蛋白沉积和路易体。在 DLB 大脑中发现的 α-突触核蛋白肽在淀粉样斑块中导致了这样一种假说，即两种肽相互作用以促进神经退行性变。在本文中，我们报告了 Aβ（1-42）和 pGlu-Aβ（3-42）对α-突触核蛋白体外聚集的影响。使用硫黄素-T 荧光测定法研究了人重组α-突触核蛋白的聚集。通过抗体缀合免疫金结合透射电子显微镜（TEM）研究了原纤维。我们的数据首次证明，在存在少量 Aβ（1-42）和 pGlu-Aβ（3-42）的情况下，α-突触核蛋白的聚集倾向显著增加，但对小鼠原代神经元没有毒性作用。通过 TEM 与肽的免疫金标记相结合对原纤维的组成进行分析，揭示了α-突触核蛋白与 Aβ在体外的相互作用，导致纤维形成加速。对动力学数据的分析表明，显著增强的核形成是造成这种影响的原因。此外，在具有淀粉样蛋白病理的老年转基因小鼠大脑中通过双重免疫荧光标记，在体内证实了病理条件下α-突触核蛋白和 Aβ以及 pGlu-Aβ的共发生。这些观察结果暗示了神经退行性变中淀粉样肽 α-突触核蛋白和 Aβ 物种之间的串扰。这种效应可能是许多痴呆症病例中 Lewy 体和斑块共发生的原因。
