临床前阿尔茨海默病中早期小胶质细胞和星形胶质细胞反应性

Early microglial and astrocyte reactivity in preclinical Alzheimer's disease.

作者信息

Fernández-Matarrubia Marta, Valera-Barrero Andrea, Renuncio-García Mónica, Aguilella Marcos, Lage Carmen, López-García Sara, Ocejo-Vinyals J Gonzalo, Martínez-Dubarbie Francisco, Molfetta Guglielmo Di, Pozueta-Cantudo Ana, García-Martínez María, Corrales-Pardo Andrea, Bravo María, López-Hoyos Marcos, Irure-Ventura Juan, Blennow Kaj, Ashton Nicholas J, Zetterberg Henrik, Sánchez-Juan Pascual, Rodríguez-Rodríguez Eloy

机构信息

Neurology Service, Marqués de Valdecilla University Hospital, Santander, Cantabria, Spain.

Institute for Research Marqués de Valdecilla (IDIVAL), Santander, Cantabria, Spain.

出版信息

Alzheimers Dement. 2025 Aug;21(8):e70502. doi: 10.1002/alz.70502.

DOI:10.1002/alz.70502

PMID:40747577

Abstract

INTRODUCTION

The role of neuroinflammation in preclinical Alzheimer's disease (AD) remains unclear.

METHODS

We assessed changes in microglial and astrocytic biomarkers in a well-characterized cohort of 211 cognitively unimpaired individuals. Structural equation modeling was used to simultaneously assess all relationships among microglial and astrocytic responses and AD pathological events.

RESULTS

Plasma glial fibrillary acidic protein (GFAP) and cerebrospinal fluid (CSF) soluble triggering receptor expressed on myeloid cells 2 (sTREM2) were increased in preclinical AD. Plasma GFAP showed an inverse bidirectional relationship with CSF amyloid beta (Aβ)42/40. CSF sTREM2 directly influenced CSF phosphorylated tau-181 (p-tau181) and neurogranin, and correlated with CSF S100 calcium-binding protein beta (S100β). CSF chitinase-3-like protein 1 (YKL-40) mediated the association between CSF p-tau181 and total tau (t-tau), whereas CSF S100β and neurofilament light showed mutual influence.

DISCUSSION

Our findings suggest that microglial and astrocyte reactivity, measured through fluid biomarkers, occur early and impact the amyloid cascade on the preclinical Alzheimer´s continuum. Specifically, GFAP influences amyloid accumulation, sTREM2 promotes tau pathology, and YKL-40 and S100β contribute to the progression of downstream neurodegenerative changes.

HIGHLIGHTS

Preclinical Alzheimer's disease (AD) showed increased levels of plasma glial fibrillary acidic protein (GFAP) and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) compared to cerebrospinal fluid (CSF) in healthy subjects. Higher plasma GFAP levels was directly associated with lower CSF amyloid beta (Aβ)42/Aβ40. Higher CSF sTREM2 concentrations increased CSF phosphorylated tau-181. Chitinase-3-like protein 1 (YKL-40) mediated tau-induced neurodegeneration. S100 calcium-binding protein beta (S100β) was directly linked to higher neurofilament light (NfL) and showed a mutual relationship with sTREM2.

摘要

引言

神经炎症在临床前阿尔茨海默病（AD）中的作用仍不明确。

方法

我们评估了211名认知未受损个体组成的特征明确队列中，小胶质细胞和星形胶质细胞生物标志物的变化。采用结构方程模型同时评估小胶质细胞和星形胶质细胞反应与AD病理事件之间的所有关系。

结果

临床前AD患者血浆胶质纤维酸性蛋白（GFAP）和脑脊液（CSF）中髓系细胞上表达的可溶性触发受体2（sTREM2）升高。血浆GFAP与脑脊液淀粉样β蛋白（Aβ）42/40呈反向双向关系。脑脊液sTREM2直接影响脑脊液磷酸化tau-181（p-tau181）和神经颗粒素，并与脑脊液S100钙结合蛋白β（S100β）相关。脑脊液几丁质酶-3样蛋白1（YKL-40）介导脑脊液p-tau181与总tau（t-tau）之间的关联，而脑脊液S100β和神经丝轻链表现出相互影响。

讨论

我们的研究结果表明，通过体液生物标志物测量的小胶质细胞和星形胶质细胞反应性在早期出现，并影响临床前阿尔茨海默病连续过程中的淀粉样蛋白级联反应。具体而言，GFAP影响淀粉样蛋白积累，sTREM2促进tau病理改变，YKL-40和S100β促成下游神经退行性变的进展。

要点

与健康受试者的脑脊液（CSF）相比，临床前阿尔茨海默病（AD）患者血浆胶质纤维酸性蛋白（GFAP）和髓系细胞上表达的可溶性触发受体2（sTREM2）水平升高。血浆GFAP水平较高与脑脊液淀粉样β蛋白（Aβ）42/Aβ40较低直接相关。脑脊液sTREM2浓度较高会增加脑脊液磷酸化tau-181。几丁质酶-3样蛋白1（YKL-40）介导tau诱导的神经退行性变。S100钙结合蛋白β（S100β）与较高的神经丝轻链（NfL）直接相关，并与sTREM2表现出相互关系。