Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO, 63110, United States.
Proteomics Center of Excellence, Northwestern University, Evanston, IL, United States.
Sci Rep. 2017 Aug 25;7(1):9520. doi: 10.1038/s41598-017-10422-x.
Amyloid-beta (Aβ) plays a key role in the pathogenesis of Alzheimer's disease (AD), but little is known about the proteoforms present in AD brain. We used high-resolution mass spectrometry to analyze intact Aβ from soluble aggregates and insoluble material in brains of six cases with severe dementia and pathologically confirmed AD. The soluble aggregates are especially relevant because they are believed to be the most toxic form of Aβ. We found a diversity of Aβ peptides, with 26 unique proteoforms including various N- and C-terminal truncations. N- and C-terminal truncations comprised 73% and 30%, respectively, of the total Aβ proteoforms detected. The Aβ proteoforms segregated between the soluble and more insoluble aggregates with N-terminal truncations predominating in the insoluble material and C- terminal truncations segregating into the soluble aggregates. In contrast, canonical Aβ comprised the minority of the identified proteoforms (15.3%) and did not distinguish between the soluble and more insoluble aggregates. The relative abundance of many truncated Aβ proteoforms did not correlate with post-mortem interval, suggesting they are not artefacts. This heterogeneity of Aβ proteoforms deepens our understanding of AD and offers many new avenues for investigation into pathological mechanisms of the disease, with implications for therapeutic development.
淀粉样蛋白-β（Aβ）在阿尔茨海默病（AD）的发病机制中起着关键作用，但人们对 AD 脑中存在的 Aβ 蛋白形式知之甚少。我们使用高分辨率质谱法分析了来自 6 例严重痴呆和经病理证实的 AD 患者脑中可溶性聚集物和不溶性物质的完整 Aβ。可溶性聚集物尤其重要，因为它们被认为是 Aβ 毒性最强的形式。我们发现了多种 Aβ 肽，包括 26 种独特的蛋白形式，包括各种 N-和 C-末端截断。N-和 C-末端截断分别占检测到的总 Aβ 蛋白形式的 73%和 30%。Aβ 蛋白形式在可溶性和更不溶性聚集物之间分离，N-末端截断主要存在于不溶性物质中，C-末端截断则分离到可溶性聚集物中。相比之下，经典 Aβ 构成了所鉴定的蛋白形式的少数（15.3%），且不能区分可溶性和更不溶性的聚集物。许多截断的 Aβ 蛋白形式的相对丰度与死后间隔时间没有相关性，表明它们不是人为因素造成的。Aβ 蛋白形式的这种异质性加深了我们对 AD 的理解，并为研究疾病的病理机制提供了许多新途径，对治疗开发具有重要意义。
