Elucidating the Role of Trem2 in Lipid Metabolism and Neuroinflammation

作者：Chenhui Zhao, Wei Qi, Xiaoping Lv, Xueli Gao, Chaonan Liu, Shimin Zheng · 发表于：CNS Neuroscience & Therapeutics · 年份：2025 · DOI：10.1111/cns.70338 · 被引用次数：8 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Neurogenesis and neuroplasticity mechanisms、Inflammation biomarkers and pathways

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive impairment and neuroinflammation. Astrocytes play a key role in the neuroinflammatory environment of AD, especially through lipid metabolism regulation. However, the mechanisms by which astrocytes, particularly through the triggering receptor expressed on myeloid cells 2 (Trem2) receptor, contribute to lipid dysregulation and neuroinflammation in AD remain inadequately understood. METHODS: We employed an AD mouse model and integrated single-cell RNA sequencing (scRNA-seq), transcriptomics, and high-throughput metabolomics to analyze lipid metabolism and inflammatory profiles in astrocytes. Differential gene expression was further validated with the GEO database, and in vitro and in vivo experiments were conducted to assess the impact of Trem2 modulation on astrocytic inflammation and lipid composition. RESULTS: Our findings demonstrate that Trem2 modulates lipid metabolism in astrocytes, affecting fatty acid and phospholipid pathways. In the AD model, Trem2 expression was suppressed, enhancing nuclear factor-κB (NF-κB) signaling and promoting the secretion of pro-inflammatory factors such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Trem2 overexpression reduced astrocytic inflammation and altered lipid composition, attenuating neuroinflammation both in vitro and in vivo. These results underscore Trem2's regulatory role in lipid metabolism and its significant impact ...