测试异天冬氨酸与阿尔茨海默病病因之间的联系。

Testing the link between isoaspartate and Alzheimer's disease etiology.

作者信息

Wang Jijing, Guo Cong, Meng Zhaowei, Zwan Marissa D, Chen Xin, Seelow Sven, Lundström Susanna L, Rodin Sergey, Teunissen Charlotte E, Zubarev Roman A

机构信息

Department of Medical Biophysics and Biochemistry, Karolinska Institutet, Stockholm, Sweden.

Department of Physics and International Centre for Quantum and Molecular Structures, College of Sciences, Shanghai University, Shanghai, China.

出版信息

Alzheimers Dement. 2023 Apr;19(4):1491-1502. doi: 10.1002/alz.12735. Epub 2022 Aug 4.

DOI:10.1002/alz.12735

PMID:35924765

Abstract

Isoaspartate (isoAsp) is a damaging amino acid residue formed in proteins as a result of spontaneous deamidation. IsoAsp disrupts protein structures, making them prone to aggregation. Here we strengthened the link between isoAsp and Alzheimer's disease (AD) by novel approaches to isoAsp analysis in human serum albumin (HSA), the most abundant blood protein and a major carrier of amyloid beta (Aβ) and phosphorylated tau (p-tau) in blood. We discovered a reduced amount of anti-isoAsp antibodies (P < 0.0001), an elevated isoAsp level in HSA (P < 0.001), more HSA aggregates (P < 0.0001), and increased levels of free Aβ (P < 0.01) in AD blood compared to controls. We also found that deamidation significantly reduces HSA capacity to bind with Aβ and p-tau (P < 0.05). These suggest the presence in AD of a bottleneck in clearance of Aβ and p-tau, leading to their increased concentrations in the brain and facilitating their aggregations there.

摘要

异天冬氨酸（isoAsp）是蛋白质中由于自发脱酰胺作用而形成的一种有害氨基酸残基。异天冬氨酸会破坏蛋白质结构，使其易于聚集。在这里，我们通过对人血清白蛋白（HSA）进行异天冬氨酸分析的新方法，加强了异天冬氨酸与阿尔茨海默病（AD）之间的联系。HSA是血液中含量最丰富的蛋白质，也是血液中淀粉样β蛋白（Aβ）和磷酸化tau蛋白（p-tau）的主要载体。我们发现，与对照组相比，AD患者血液中抗异天冬氨酸抗体的量减少（P < 0.0001），HSA中的异天冬氨酸水平升高（P < 0.001），HSA聚集体更多（P < 0.0001），游离Aβ水平升高（P < 0.01）。我们还发现，脱酰胺作用显著降低了HSA与Aβ和p-tau结合的能力（P < 0.05）。这些结果表明，AD患者存在Aβ和p-tau清除的瓶颈，导致它们在大脑中的浓度升高，并促进它们在大脑中的聚集。