Departamento de Neuroquímica, Instituto de Investigaciones Biológicas Clemente Estable (IIBCE), Montevideo, Uruguay; Área de Matemática - DETEMA, Facultad de Química, Universidad de la República, Montevideo, Uruguay.
I&D Biomédico y Químico Farmacéutico, Centro Uruguayo de Imagenología Molecular (CUDIM), Montevideo, Uruguay.
J Proteomics. 2025 Jan 6;310:105336. doi: 10.1016/j.jprot.2024.105336. Epub 2024 Oct 23.
Alzheimer's disease (AD) is the most common form of dementia, affecting approximately 47 M people worldwide. Histological features and genetic risk factors, among other evidence, supported the amyloid hypothesis of the disease. This neuronocentric paradigm is currently undergoing a shift, considering evidence of the role of other cell types, such as microglia and astrocytes, in disease progression. Previously, we described a particular astrocyte subtype obtained from the 3xTg-AD murine model that displays neurotoxic properties in vitro. We continue here our exploratory analysis through the lens of metabolomics to identify potentially altered metabolites and biological pathways. Cell extracts from neurotoxic and control astrocytes were compared using high-resolution mass spectrometry-based metabolomics. Around 12 % of metabolic features demonstrated significant differences between neurotoxic and control astrocytes, including alterations in the key metabolite glutamate. Consistent with our previous transcriptomic study, the present results illustrate many homeostatic and regulatory functions of metabolites, suggesting that neurotoxic 3xTg-AD astrocytes exhibit alterations in the Krebs cycle as well as the prostaglandin pathway. This is the first metabolomic study performed in 3xTg-AD neurotoxic astrocytes. These results provide insight into metabolic alterations potentially associated with neurotoxicity and pathology progression in the 3xTg-AD mouse model and strengthen the therapeutic potential of astrocytes in AD. BIOLOGICAL SIGNIFICANCE: Our study is the first high-resolution metabolomic characterization of the novel neurotoxic 3xTg-AD astrocytes. We propose key metabolites and pathway alterations, as well as possible associations with gene expression alterations in the model. Our results are in line with recent hypotheses beyond the amyloid cascade, considering the involvement of several stress response cascades during the development of Alzheimer's disease. This work could inspire other researchers to initiate similar studies in related models. Furthermore, this work illustrates a powerful workflow for metabolite annotation and selection that can be implemented in other studies.
阿尔茨海默病（AD）是最常见的痴呆症形式，影响全球约 4700 万人。组织学特征和遗传风险因素等证据支持疾病的淀粉样蛋白假说。这种以神经元为中心的范式目前正在发生转变，考虑到其他细胞类型（如小胶质细胞和星形胶质细胞）在疾病进展中的作用的证据。以前，我们从 3xTg-AD 小鼠模型中描述了一种特殊的星形胶质细胞亚型，该亚型在体外具有神经毒性。我们继续通过代谢组学的视角进行探索性分析，以确定潜在改变的代谢物和生物途径。使用基于高分辨率质谱的代谢组学比较神经毒性和对照星形胶质细胞的细胞提取物。约 12%的代谢特征在神经毒性和对照星形胶质细胞之间表现出显著差异，包括关键代谢物谷氨酸的变化。与我们之前的转录组学研究一致，本研究结果说明了代谢物的许多动态平衡和调节功能，表明神经毒性 3xTg-AD 星形胶质细胞表现出三羧酸循环以及前列腺素途径的改变。这是在 3xTg-AD 神经毒性星形胶质细胞中进行的第一项代谢组学研究。这些结果提供了与 3xTg-AD 小鼠模型中的神经毒性和病理进展相关的代谢改变的见解，并增强了星形胶质细胞在 AD 中的治疗潜力。生物学意义：我们的研究是对新型神经毒性 3xTg-AD 星形胶质细胞的首次高分辨率代谢组学表征。我们提出了关键代谢物和途径的改变，以及与模型中基因表达改变的可能关联。我们的结果与淀粉样蛋白级联之外的最近假说一致，考虑到在阿尔茨海默病的发展过程中涉及几个应激反应级联。这项工作可以启发其他研究人员在相关模型中启动类似的研究。此外，这项工作说明了一种用于代谢物注释和选择的强大工作流程，可在其他研究中实施。
