WDR49阳性星形胶质细胞标志额颞叶变性及阿尔茨海默病中神经退行性病变的严重程度

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中文摘要：最近在具有GRN致病变异的额颞叶变性(FTLD)中鉴定出一类表达WD重复结构域49(WDR49)的星形胶质细胞亚群.本研究是首次调查这些细胞在其他FTLD亚型和阿尔茨海默病(AD)中的表达及其与病理关系的研究.研究对一组死后脑组织样本进行了免疫组织化学和免疫荧光分析,样本包括TDP-43蛋白病患者(12例GRN、11例C9orf72、9例散发性TDP-43)、tau蛋白病患者(13例MAPT、8例散发性tau)、10例AD患者和4例对照组,分析部位为额叶、颞叶和枕叶皮质切片中的WDR49和病理性包涵体.研究计算了WDR49阳性细胞数(每平方毫米调整值),并研究了其与TDP-43/tau病理数字化定量面积百分比和神经退行性病变半定量评分的相关性.对WDR49和病理性包涵体进行了定量共定位分析.在FTLD各亚型和AD的大脑实质和(周)血管间隙中均存在WDR49阳性星形胶质细胞,它们具有不同的形态模式,尤其在灰质中富集.在对照组中,发现散在的WDR49阳性细胞包裹着血管.在GRN病例的额叶皮质(FC)、GRN、AD和散发性原发性tau蛋白病的颞叶皮质中,WDR49阳性星形胶质细胞数量最多.在枕叶皮质中,各组中仅发现少量细胞.WDR49阳性星形胶质细胞数量与神经退行性病变和TDP-43病理的严重程度呈正相关,但与tau蛋白病无关.此外,在前额叶和颞叶皮质中,WDR49与TDP-43(14%～21%)和tau(31%～45%)部分共定位.总之,WDR49是FTLD和AD中不同形态星形胶质细胞亚群的标志物,反映了神经退行性病变的严重程度.这些星形胶质细胞可能对病理损伤产生反应而活化,并从血管壁迁移到实质中.

外文标题：WDR49-Positive Astrocytes Mark Severity of Neurodegeneration in Frontotemporal Lobar Degeneration and Alzheimer's Disease

外文摘要：A subpopulation of astrocytes expressing WD Repeat Domain 49(WDR49)was recently identified in fronto-temporal lobar degeneration(FTLD)with GRN pathogenic variants.This is the first study to investigate their expression and relation to pathology in other FTLD subtypes and Alzheimer's disease(AD).In a postmortem cohort of TDP-43 pro-teinopathies(12 GRN,11 C9orf72,9 sporadic TDP-43),tauopathies(13 MAPT,8 sporadic tau),10 AD,and four con-trols,immunohistochemistry and immunofluorescence were performed for WDR49 and pathological inclusions on fron-tal,temporal,and occipital cortical sections.WDR49-positive cell counts(adjusted per mm2)were examined and related to digitally quantified percentage areas of TDP-43/tau pathology and semiquantitative scores of neurodegeneration.Quantitative colocalization analysis of WDR49 and pathological inclusions was done.WDR49-positive astrocytes were present across FTLD subtypes and AD in the brain parenchyma and(peri-)vascular space,with distinct morphological patterns,and were particularly enriched in gray matter.In controls,sporadic WDR49-positive cells were found envelop-ing vessels.WDR49-positive astrocytes were most abundant in the frontal cortex(FC)of GRN cases and temporal cor-tex in GRN,AD,and sporadic primary tauopathy.In the occipital cortex,only a few cells were found across groups.WDR49-positive astrocyte counts positively correlated with the severity of neurodegeneration and TDP-43 pathology but not tauopathy.Furthermore,in frontotemporal cortices,WDR49 partly colocalized with TDP-43(14%-21%)and tau(31%-45%).In conclusion,WDR49 is a marker for a subset of astrocytes with different morphologies across FTLD and AD,reflecting the severity of neurodegeneration.These astrocytes may become activated in neurodegeneration in re-sponse to pathological damage and migrate from the vessel wall to the parenchyma.

外文关键词：

Alzheimer's diseaseWDR49astrocytesfrontotemporal lobar degeneration

作者：

Ana Rajicic、Lucia A A Giannini、Emma Gerrits、Renee van Buuren、Shamiram Melhem、Johan A Slotman、Annemieke J M Rozemuller、Bart J L Eggen、John C van Swieten、Harro Seelaar、王晶

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作者单位：

Department of Neurology and Alzheimer Centre Erasmus MC,Erasmus MC University Medical Center,Rotterdam,the Netherlands

Department of Neuroscience,Karolinska Institutet,Stockholm,Sweden

Department of Pathology and Erasmus Optical Imaging Center,Erasmus MC University Medical Center,Rotterdam,the Netherlands

Department of Pathology,Amsterdam Neuroscience,Amsterdam University Medical Center,Amsterdam,The Netherlands

Department of Biomedical Sciences of Cells&Systems,Section of Molecular Neurobiology,University of Groningen and University Medical Center Groningen,Groningen,Netherlands

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关键词：

阿尔茨海默病 WDR49 星形胶质细胞额颞叶变性

出版年：

2025

DOI：

10.16780/j.cnki.sjssgncj.202501015

神经损伤与功能重建

华中科技大学同济医学院

神经损伤与功能重建

影响因子：0.977

ISSN：1001-117X

年,卷(期)：2025.20(1)