Levin Yishai, Tickotsky Nili, Morgenstern David, Wolf-Levy Hila, Markus Barak, Cooper Itzik, Reiner-Benaim Anat, Uribarri Jaime, Unger Ron, Buchman Aron S, Beeri Michal Schnaider
The de Botton Institute for Protein Profiling, Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel.
The Joseph Sagol Neuroscience Center, Sheba Medical Center, Ramat Gan, Israel.
PLoS One. 2025 May 8;20(5):e0318916. doi: 10.1371/journal.pone.0318916. eCollection 2025.
Type 2 diabetes (T2D) is consistently related to an increased risk of cognitive decline and dementia. However, the molecular underpinnings of this association remain poorly understood. In this study, we applied a novel mass spectrometry-based glycoproteomic methodology to profile serum glycoproteins in older adults with T2D, aiming to identify glycopeptiforms associated with cognitive impairment. Our method allowed comprehensive profiling of N glycosylation in addition to the unique ability to profile glycation events on specific amino acid sites. Serum samples from initially cognitively normal older adults with T2D were collected, with participants classified as cognitive decliners (who developed impairment) and non-decliners (who maintained normal cognition over time). We identified significant differences in the abundance of glycopeptiforms between these groups, noting that certain glycopeptiforms exhibited unique changes over time in decliners. We identified 13 glycopeptiforms that exhibited significant differences between the groups both at baseline and in their rates of change over time. Pathway analysis indicated that glycation events were linked to metabolic pathways while glycosylation to immune-related pathways, aligning with established links between these processes and cognitive decline. This study offers new insights into glycoproteoform alterations in older adults with T2D experiencing cognitive decline. It highlights the potential of specific glycopeptiforms as biomarkers for early cognitive impairment in T2D. Further validation in larger cohorts will enhance our understanding of glycosylation and glycation in T2D and potentially lead to the discovery of novel treatment targets for T2D-related cognitive decline. Raw data and search are available via ProteomeXchange with identifier PXD050780.
2型糖尿病（T2D）一直与认知能力下降和痴呆风险增加有关。然而，这种关联的分子基础仍知之甚少。在本研究中，我们应用了一种基于质谱的新型糖蛋白质组学方法来分析T2D老年患者的血清糖蛋白，旨在识别与认知障碍相关的糖肽形式。我们的方法不仅能够全面分析N-糖基化，还具有分析特定氨基酸位点糖基化事件的独特能力。收集了最初认知正常的T2D老年患者的血清样本，参与者被分为认知衰退者（出现认知障碍）和非衰退者（随时间保持正常认知）。我们发现这些组之间糖肽形式的丰度存在显著差异，注意到某些糖肽形式在衰退者中随时间呈现出独特的变化。我们确定了13种糖肽形式，它们在基线时以及随时间的变化率上在两组之间均表现出显著差异。通路分析表明，糖基化事件与代谢通路相关，而糖基化与免疫相关通路相关，这与这些过程和认知衰退之间已确立的联系一致。本研究为经历认知衰退的T2D老年患者糖蛋白变体的改变提供了新的见解。它突出了特定糖肽形式作为T2D早期认知障碍生物标志物的潜力。在更大队列中的进一步验证将增强我们对T2D中糖基化和糖基化的理解，并可能导致发现T2D相关认知衰退的新治疗靶点。原始数据和搜索可通过ProteomeXchange获得，标识符为PXD050780。
