近日，加拿大麦吉尔大学Eduardo R. Zimmer及其课题组的最新研究揭示了小胶质细胞调节阿尔茨海默病中Aβ依赖性星形胶质细胞的反应性。这一研究成果于2025年11月6日发表在国际顶尖学术期刊《自然—神经科学》上。

在这项研究中，课题组人员研究了阿尔茨海默症个体中小胶质细胞激活和淀粉样蛋白-β (Aβ)与反应性星形胶质细胞形成之间的关系。研究人员对101名个体进行了正电子发射断层扫描，以评估Aβ沉积（[18F]AZD4694）、tau聚集（[18F] mark -6240）和小胶质细胞活化（[11C]PBR28），以及星形胶质细胞反应性（GFAP）和tau磷酸化（p-tau217）的血浆生物标志物。

该团队进一步评估了251例脑脊液中小胶质标志物sTREM2的水平。该课题组研究人员发现，只有在小胶质细胞激活的情况下，Aβ病理才与星形胶质细胞的反应性有关。Aβ对星形胶质细胞反应性的小胶质依赖性作用通过tau磷酸化和聚集进一步与认知障碍相关。他们的研究结果表明，小胶质细胞激活在Aβ相关星形胶质细胞反应中起关键作用，而星形胶质细胞反应反过来又有助于AD的下游病理特征。

据悉，实验证据表明，激活的小胶质细胞在神经退行性疾病，如阿尔茨海默病（AD）中诱导星形胶质细胞反应。

附：英文原文

Title: Microglia modulate Aβ-dependent astrocyte reactivity in Alzheimer’s disease

Author: Ferrari-Souza, Joo Pedro, Povala, Guilherme, Rahmouni, Nesrine, Bellaver, Bruna, Ferreira, Pamela C. L., De Bastiani, Marco Antnio, Leffa, Douglas T., Lussier, Firoza Z., Aguzzoli, Cristiano S., Brum, Wagner S., Carello-Collar, Giovanna, Borelli, Wyllians V., Therriault, Joseph, Macedo, Arthur C., Servaes, Stijn, Stevenson, Jenna, Pola, Ilaria, Gauthier, Serge, Souza, Diogo O., Schilling, Lucas Porcello, Lourenco, Mychael V., Triana-Baltzer, Gallen, Kolb, Hartmuth C., Benedet, Andra L., Ashton, Nicholas J., Tudorascu, Dana L., Zetterberg, Henrik, Blennow, Kaj, Johnson, Sterling C., Pascoal, Tharick A., Rosa-Neto, Pedro, Zimmer, Eduardo R.

Issue&Volume: 2025-11-06

Abstract: Experimental evidence suggests that activated microglia induce astrocyte reactivity in neurodegenerative disorders, such as Alzheimer’s disease (AD). In this study, we investigated the association between microglial activation and amyloid-β (Aβ) with reactive astrogliosis in individuals across the AD spectrum. We examined 101 individuals using positron emission tomography radiotracers to assess Aβ deposition ([18F]AZD4694), tau aggregation ([18F]MK-6240) and microglial activation ([11C]PBR28), along with plasma biomarkers for astrocyte reactivity (GFAP) and tau phosphorylation (p-tau217). We further evaluated 251 individuals with cerebrospinal fluid levels of the microglial marker sTREM2. We found that Aβ pathology was associated with astrocyte reactivity across cortical brain regions only in the presence of microglial activation. The microglia-dependent effects of Aβ on astrocyte reactivity were further related to cognitive impairment through tau phosphorylation and aggregation. Our results suggest that microglial activation plays a key role in Aβ-related astrocyte reactivity, which, in turn, contributes to downstream pathological features of AD.

DOI: 10.1038/s41593-025-02103-0

Source: https://www.nature.com/articles/s41593-025-02103-0