Joshua E Mayfield, Alexander J Rajic, Patricia Aguilar-Calvo, Katrin Soldau, Samantha Flores, Roger Lawrence, Biwsa Choudhury, Majid Ghassemian, Donald P Pizzo, Steven L Wagner, Garrett A Danque, Paige Sumowski, Lawrence A Hansen, Vanessa Goodwill, Jeffery D Esko, Christina J Sigurdson
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引用次数: 0
摘要
脑淀粉样血管病(CAA)是阿尔茨海默病的共同特征,其中淀粉样蛋白β (a β)沉积在脑和脑膜血管壁,易使血管发生微出血和大出血。血管壁含有不同的蛋白质和硫酸肝素(HS),但血管蛋白和HS如何与Aβ联合尚不清楚。我们进行了首次多组学研究,系统地表征了23例中重度CAA患者和对照组的蛋白以及HS丰度、硫酸化水平和双糖组成。然后,我们分析了Aβ与其他蛋白、HS和载脂蛋白E基因型之间的关系。我们发现含有未取代氨基葡萄糖的小HS双糖以及6-O硫酸双糖增加;Aβ40水平与未取代氨基葡萄糖呈正相关。来自脑实质或血浆的细胞外蛋白也有增加,包括嗅觉蛋白样蛋白3、纤维蛋白原、血清淀粉样蛋白、载脂蛋白E和分泌的卷曲相关蛋白3。我们的研究结果表明,受caa影响的小脑膜血管的HS和蛋白质特异性改变,为研究与a β沉积共同发生的细胞外重塑提供了分子视角,并可能为生前诊断检测的开发和阻止a β-HS相互作用的治疗策略提供了基础。
Multi-omic analysis of meningeal cerebral amyloid angiopathy reveals enrichment of unsubstituted glucosamine and extracellular proteins.
Cerebral amyloid angiopathy (CAA) is a common feature of Alzheimer's disease in which amyloid-β (Aβ) deposits in cerebral and leptomeningeal vessel walls, predisposing vessels to micro- and macro-hemorrhages. The vessel walls contain distinct proteins and heparan sulfate (HS), yet how vascular proteins and HS jointly associate with Aβ is unknown. We conducted the first multi-omics study to systematically characterize the proteins as well as the HS abundance, sulfation level, and disaccharide composition of leptomeninges from 23 moderate to severe CAA cases and controls. We then analyzed the associations between Aβ and other proteins, HS, and apolipoprotein E genotype. We found an increase in a minor HS disaccharide containing unsubstituted glucosamine, as well as 6-O sulfated disaccharides; Aβ40 levels positively correlated with unsubstituted glucosamine. There was also an increase in extracellular proteins derived from brain parenchyma or plasma, including olfactomedin-like protein 3, fibrinogen, serum amyloid protein, apolipoprotein E, and secreted frizzled related protein-3. Our findings of vascular HS and protein alterations specific to CAA-affected leptomeningeal vessels provide molecular insight into the extracellular remodeling that co-occurs with Aβ deposits and may indicate a basis for antemortem diagnostic assay development and therapeutic strategies to impede Aβ-HS interactions.
期刊介绍:
Journal of Neuropathology & Experimental Neurology is the official journal of the American Association of Neuropathologists, Inc. (AANP). The journal publishes peer-reviewed studies on neuropathology and experimental neuroscience, book reviews, letters, and Association news, covering a broad spectrum of fields in basic neuroscience with an emphasis on human neurological diseases. It is written by and for neuropathologists, neurologists, neurosurgeons, pathologists, psychiatrists, and basic neuroscientists from around the world. Publication has been continuous since 1942.