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Testing the link between isoaspartate and Alzheimer's disease etiology
Alzheimer's & Dementia ( IF 14.0 ) Pub Date : 2022-08-04 , DOI: 10.1002/alz.12735
Jijing Wang 1 , Cong Guo 2 , Zhaowei Meng 1 , Marissa D Zwan 3 , Xin Chen 2 , Sven Seelow 1 , Susanna L Lundström 1 , Sergey Rodin 1, 4 , Charlotte E Teunissen 3 , Roman A Zubarev 1, 5, 6
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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.

中文翻译:

检测异天冬氨酸与阿尔茨海默病病因学之间的联系

异天冬氨酸 (isoAsp) 是由于自发脱酰胺而在蛋白质中形成的破坏性氨基酸残基。IsoAsp 破坏蛋白质结构,使它们易于聚集。在这里,我们通过人血清白蛋白 (HSA) 中 isoAsp 分析的新方法加强了 isoAsp 和阿尔茨海默病 (AD) 之间的联系,HSA 是最丰富的血液蛋白,也是淀粉样蛋白 β (Aβ) 和磷酸化 tau (p-tau) 的主要载体在血液中。我们发现抗 isoAsp 抗体的量减少 ( P < 0.0001),HSA 中的 isoAsp 水平升高 ( P < 0.001),HSA 聚集体增多 ( P < 0.0001),游离 Aβ 水平升高 ( P <0.01) 在 AD 血液中与对照相比。我们还发现脱酰胺显着降低了 HSA 与 Aβ 和 p-tau 结合的能力 ( P < 0.05)。这些表明 AD 中存在清除 Aβ 和 p-tau 的瓶颈,导致它们在大脑中的浓度增加并促进它们在那里的聚集。
更新日期:2022-08-04
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