在衰老和阿尔茨海默病过程中，神经胶质反应与突触功能障碍相关。

Glial reactivity correlates with synaptic dysfunction across aging and Alzheimer's disease.

作者信息

Rohden Francieli, Ferreira Pamela C L, Bellaver Bruna, Ferrari-Souza João Pedro, Aguzzoli Cristiano S, Soares Carolina, Abbas Sarah, Zalzale Hussein, Povala Guilherme, Lussier Firoza Z, Leffa Douglas T, Bauer-Negrini Guilherme, Rahmouni Nesrine, Tissot Cécile, Therriault Joseph, Servaes Stijn, Stevenson Jenna, Benedet Andrea L, Ashton Nicholas J, Karikari Thomas K, Tudorascu Dana L, Zetterberg Henrik, Blennow Kaj, Zimmer Eduardo R, Souza Diogo, Rosa-Neto Pedro, Pascoal Tharick A

机构信息

Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.

Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.

出版信息

Nat Commun. 2025 Jul 1;16(1):5653. doi: 10.1038/s41467-025-60806-1.

DOI:10.1038/s41467-025-60806-1

PMID:40593718

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12215965/

Abstract

Previous studies suggest glial and neuronal changes may trigger synaptic dysfunction in Alzheimer's disease (AD), but the link between their markers and synaptic abnormalities in the living brain remains unclear. We investigated the association between glial reactivity and synaptic dysfunction biomarkers in cerebrospinal fluid (CSF) from 478 individuals in cognitively unimpaired (CU) and cognitively impaired (CI) individuals. We measured amyloid-β (Aβ), phosphorylated tau (pTau181), astrocyte reactivity (GFAP), microglial activation (sTREM2), and synaptic markers (GAP43, neurogranin). CSF GFAP levels were associated with presynaptic and postsynaptic dysfunction, independent of cognitive status or Aβ presence. CSF sTREM2 levels were related to presynaptic markers in cognitively unimpaired and impaired Aβ+ individuals, and to postsynaptic markers in cognitively impaired Aβ+ individuals. Notably, CSF pTau mediated the relationships between GFAP or sTREM2 and synaptic dysfunction. Our findings, validated in two independent cohorts (TRIAD and ADNI), reveal a distinct pattern of glial contribution to synaptic degeneration.

摘要

先前的研究表明，胶质细胞和神经元的变化可能会引发阿尔茨海默病（AD）中的突触功能障碍，但它们的标志物与活体大脑中突触异常之间的联系仍不清楚。我们调查了478名认知未受损（CU）和认知受损（CI）个体脑脊液（CSF）中胶质细胞反应性与突触功能障碍生物标志物之间的关联。我们测量了淀粉样β蛋白（Aβ）、磷酸化tau蛋白（pTau181）、星形胶质细胞反应性（GFAP）、小胶质细胞激活（sTREM2）和突触标志物（GAP43、神经颗粒素）。脑脊液GFAP水平与突触前和突触后功能障碍相关，与认知状态或Aβ的存在无关。脑脊液sTREM2水平与认知未受损和Aβ阳性受损个体的突触前标志物相关，与认知受损Aβ阳性个体的突触后标志物相关。值得注意的是，脑脊液pTau介导了GFAP或sTREM2与突触功能障碍之间的关系。我们在两个独立队列（TRIAD和ADNI）中验证的研究结果揭示了胶质细胞对突触退化的独特作用模式。