Cerebral small vessel disease is a common condition linked to dementia and stroke. As an age-dependent brain pathology, cerebral SVD may share molecular processes with core neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Many neurodegenerative diseases feature abnormal protein accumulation and aberrant protein folding, resulting in multimerization of specific proteins. We investigated if a small NOTCH3 N-terminal fragment (NTF) that co-registers with pathologically affected cells in the inherited SVD, CADASIL, is capable of multimerization. We also characterized endogenous small molecule vascular enhancers and inhibitors of multimerization. NTF multimerizes spontaneously and also forms conjugates with vascular catecholamines, including dopamine and norepinephrine, which avidly promote multimerization of the protein. Inhibition of catecholamine-dependent multimerization by vitamin C and reversal by reducing agents implicate an essential role of oxidation in NTF multimerization. Antibodies that react with degenerating arteries in CADASIL tissue preferentially bind to multimerized forms of NTF. These studies suggest that multimerization of proteins in the aging brain is not restricted to neuronal molecules and may participate in age-dependent vascular pathology.

中文翻译：

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硫醇介导和儿茶酚胺增强的脑血管疾病的多聚体富含NOTCH3片段。

脑小血管疾病是与痴呆和中风有关的常见疾病。作为年龄依赖性的脑病理学，脑SVD可能与核心神经退行性疾病（如阿尔茨海默氏病和帕金森氏病）共享分子过程。许多神经退行性疾病以异常的蛋白质积累和异常的蛋白质折叠为特征，导致特定蛋白质的多聚化。我们调查了一个小的NOTCH3 N末端片段（NTF）与遗传性SVD中受病理影响的细胞CADASIL共注册的能力是否能够进行多聚化。我们还表征了内源性小分子血管增强剂和多聚化抑制剂。NTF自发地聚合，并且还与包括多巴胺和去甲肾上腺素在内的血管儿茶酚胺形成结合物，从而强烈促进蛋白质的多聚化。维生素C对儿茶酚胺依赖性多聚体的抑制和还原剂的逆转暗示了NTF多聚体中氧化的重要作用。与CADASIL组织中的退化动脉反应的抗体优先结合NTF的多聚形式。这些研究表明，衰老的大脑中蛋白质的多聚化不仅限于神经元分子，而且可能参与了年龄依赖性血管病变。