Segura-Collar Berta, Mondejar-Ruescas Lucia, Alcivar-López Denisse, Garranzo-Asensio María, Mata-Martinez Pablo, Garcia-Escudero Ramón, Hernández-Laín Aurelio, Sepúlveda Juan M, Nuñez Ángel Pérez, Avila Jesús, Sánchez-Gómez Pilar, Gargini Ricardo
Instituto de Investigaciones Biomédicas I+12, (Imas12) Hospital 12 de Octubre, Madrid, Spain; Dpto Anatomía Patológica, Hospital 12 de Octubre, Madrid, Spain.
Neurooncology Unit, Instituto de Salud Carlos III, Madrid, Spain.
EBioMedicine. 2025 Jun 27;118:105833. doi: 10.1016/j.ebiom.2025.105833.
Ageing-dependent low-grade inflammation is a hallmark of central nervous system (CNS) diseases. Vascular and immune abnormalities are implicated in the progression of gliomas and occur in the early stages of Alzheimer's disease (AD); however, the mechanisms by which these alterations manifest in the brain parenchyma remain unclear.
Using RNAseq, scRNAseq, bioinformatics tools and a cohort of patients with glioma and Alzheimer's disease for validation of results, we have established an analysis of blood-brain barrier (BBB) dysfunction and neuron loss. A mouse model for glioblastoma pathology was also used that reversed BBB disruption and neuron loss, with the incorporation of the IDH mutation. Finally, we established a characterization of the relevant immune populations with an IHC analysis and transcriptional profile.
In this study, molecular analyses of the brain ecosystem revealed that blood-brain barrier dysfunction and neuronal synapse integrity exhibit significant threshold-dependent changes that correlate directly and inversely, respectively, with brain ageing (significant changes at 57 years) and the progression of AD and gliomas (survival of 1525 vs 4084 days for patients with High vs Low BBB dysfunction). Using human samples and mouse models, we identified immunoageing processes characterized by an imbalance between pro-inflammatory and anti-inflammatory signals. This dysregulation promotes the extravasation of monocyte-derived macrophages (85% increase of cells), particularly those with a suppressive phenotype, alongside an increase in inflammatory cytokine levels. Notably, our data show that vascular normalization in a glioma model can reverse neuronal loss and attenuate the aggressiveness of the tumours. Finally, tumour development can be prevented by reactivating the ageing immune system.
We propose that the ageing brain represents a common, BBB dysfunction-associated process driving chronic inflammation. This inflammation is regulated by TREM2+/TIM3+ suppressive myeloid cells, which play a central role in disease progression. Our findings suggest that targeting these pathways could offer therapeutic strategies to mitigate CNS pathologies linked to ageing, characterized by toxic neuroinflammation and myeloid dysfunction.
This study was funded by ISCIII and co-funded by the European Union.
与衰老相关的低度炎症是中枢神经系统（CNS）疾病的一个标志。血管和免疫异常与胶质瘤的进展有关，且在阿尔茨海默病（AD）的早期阶段就已出现；然而，这些改变在脑实质中显现的机制仍不清楚。
我们使用RNA测序、单细胞RNA测序、生物信息学工具以及一组胶质瘤和阿尔茨海默病患者来验证结果，建立了血脑屏障（BBB）功能障碍和神经元丢失的分析方法。还使用了一个胶质母细胞瘤病理的小鼠模型，该模型通过引入异柠檬酸脱氢酶（IDH）突变逆转了血脑屏障破坏和神经元丢失。最后，我们通过免疫组织化学分析和转录谱建立了相关免疫群体的特征。
在本研究中，对脑生态系统的分子分析表明，血脑屏障功能障碍和神经元突触完整性呈现出显著的阈值依赖性变化，分别与脑衰老（57岁时出现显著变化）以及AD和胶质瘤的进展直接和反向相关（血脑屏障功能障碍高与低的患者生存时间分别为1525天和4084天）。使用人类样本和小鼠模型，我们确定了以促炎和抗炎信号失衡为特征的免疫衰老过程。这种失调促进了单核细胞衍生巨噬细胞的外渗（细胞增加85%），特别是那些具有抑制表型的巨噬细胞，同时炎症细胞因子水平也有所增加。值得注意的是,我们的数据表明，胶质瘤模型中的血管正常化可以逆转神经元丢失并减弱肿瘤的侵袭性。最后，通过重新激活衰老的免疫系统可以预防肿瘤的发展。
我们提出，衰老的大脑代表了一个驱动慢性炎症的、与血脑屏障功能障碍相关的共同过程。这种炎症由触发受体表达于髓样细胞2（TREM2）阳性/含T细胞免疫球蛋白黏蛋白域分子3（TIM3）阳性的抑制性髓样细胞调节，它们在疾病进展中起核心作用。我们的研究结果表明，针对这些途径可能提供治疗策略，以减轻与衰老相关的中枢神经系统病理，其特征为毒性神经炎症和髓样功能障碍。
本研究由西班牙卫生健康研究所（ISCIII）资助，并由欧盟共同资助。
