阿尔茨海默病中斑块和小胶质细胞糖基化的不同模式。

IF 5.8 2区 医学 Q1 CLINICAL NEUROLOGY
Brain Pathology Pub Date : 2024-05-09 DOI:10.1111/bpa.13267
Caitlyn Fastenau, Madison Bunce, Mallory Keating, Jessica Wickline, Sarah C. Hopp, Kevin F. Bieniek
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引用次数: 0

摘要

糖基化是大脑中最常见的翻译后修饰形式。在阿尔茨海默病(AD)病例的脑脊液和脑组织中已观察到糖基化异常,包括末端硅酸(SA)修饰的失调。虽然在 AD 中发现了糖基化的改变,但由于常用方法的空间分辨率有限,细胞或聚合体相关聚糖上的 SA 修饰定位在很大程度上是未知的。本研究旨在利用组织学技术的新组合来克服这些局限性,从而描述尸检证实的 AD 死后脑组织中 O 和 N 连接聚糖的糖基化状况。糖基化聚糖可促进重要的细胞功能,包括细胞间相互作用、细胞迁移、细胞粘附、免疫调节和膜兴奋性。以往的研究尚未同时研究神经变性中的 N-和 O-连接的糖基化聚糖。在这项研究中,我们使用定量数字病理学技术评估了 10 例 AD 患者的三个脑区(额叶皮层、海马和小脑)中糖链化聚糖的位置和分布。值得注意的是,我们发现 Aβ 斑块微环境中的 N-糖基化程度明显高于 O-糖基化程度。斑块相关的小胶质细胞在斑块病理近端显示出最强烈的 N-ialylation。进一步的分析表明,有核和弥漫性 Aβ 斑块形态的 N-和 O-ialylation水平存在明显差异。有趣的是,磷酸化 tau 病理学导致 N-ialylation略有增加,而对这些 AD 大脑中的 O-ialylation没有影响。这些发现证实了我们以前用新的组织学方法在小鼠身上观察到的结果,支持小胶质细胞苷酰化似乎与AD蛋白聚集有关系,同时为治疗策略提供了潜在的靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Distinct patterns of plaque and microglia glycosylation in Alzheimer's disease

Distinct patterns of plaque and microglia glycosylation in Alzheimer's disease

Distinct patterns of plaque and microglia glycosylation in Alzheimer's disease

Glycosylation is the most common form of post-translational modification in the brain. Aberrant glycosylation has been observed in cerebrospinal fluid and brain tissue of Alzheimer's disease (AD) cases, including dysregulation of terminal sialic acid (SA) modifications. While alterations in sialylation have been identified in AD, the localization of SA modifications on cellular or aggregate-associated glycans is largely unknown because of limited spatial resolution of commonly utilized methods. The present study aims to overcome these limitations with novel combinations of histologic techniques to characterize the sialylation landscape of O- and N-linked glycans in autopsy-confirmed AD post-mortem brain tissue. Sialylated glycans facilitate important cellular functions including cell-to-cell interaction, cell migration, cell adhesion, immune regulation, and membrane excitability. Previous studies have not investigated both N- and O-linked sialylated glycans in neurodegeneration. In this study, the location and distribution of sialylated glycans were evaluated in three brain regions (frontal cortex, hippocampus, and cerebellum) from 10 AD cases using quantitative digital pathology techniques. Notably, we found significantly greater N-sialylation of the Aβ plaque microenvironment compared with O-sialylation. Plaque-associated microglia displayed the most intense N-sialylation proximal to plaque pathology. Further analyses revealed distinct differences in the levels of N- and O-sialylation between cored and diffuse Aβ plaque morphologies. Interestingly, phosphorylated tau pathology led to a slight increase in N-sialylation and no influence of O-sialylation in these AD brains. Confirming our previous observations in mice with novel histologic approach, these findings support microglia sialylation appears to have a relationship with AD protein aggregates while providing potential targets for therapeutic strategies.

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来源期刊
Brain Pathology
Brain Pathology 医学-病理学
CiteScore
13.20
自引率
3.10%
发文量
90
审稿时长
6-12 weeks
期刊介绍: Brain Pathology is the journal of choice for biomedical scientists investigating diseases of the nervous system. The official journal of the International Society of Neuropathology, Brain Pathology is a peer-reviewed quarterly publication that includes original research, review articles and symposia focuses on the pathogenesis of neurological disease.
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