Elevated Galectin-3 Is Associated with Aging, Multiple Sclerosis, and Oxidized Phosphatidylcholine-Induced Neurodegeneration

• DOI: 10.1523/jneurosci.2312-22.2023
• Publication Date: 2023-05-19T17:50:12Z
• Authors: Sara Xue; Brian M. Lozinski; Samira Ghorbani; Khanh Ta; Charlotte D'Mello; V. Wee Yong; Yifei Dong
• Keywords: Male; Mice; Multiple Sclerosis; Encephalomyelitis, Autoimmune, Experimental; Spinal Cord; Galectin 3; Phosphatidylcholines; Animals; Female; Microglia

Aging is a significant risk factor associated with the progression of CNS neurodegenerative diseases including multiple sclerosis (MS). Microglia, resident macrophages parenchyma, are major population immune cells that accumulate in MS lesions. While they normally regulate tissue homeostasis and facilitate clearance neurotoxic molecules oxidized phosphatidylcholines (OxPCs), their transcriptome neuroprotective functions reprogrammed by aging. Thus, determining factors instigate aging microglia dysfunction can lead to new insights for promoting repair halting disease progression. Through single-cell RNA sequencing (scRNAseq), we identified Lgals3, which encodes galectin-3 (Gal3), as an age upregulated gene responding OxPC. Consistently, excess Gal3 accumulated OxPC lysolecithin-induced focal spinal cord white matter (SCWM) lesions middle-aged mice compared young mice. was also elevated mouse experimental autoimmune encephalomyelitis (EAE) more importantly brain from two male one female individuals. delivery alone into did not induce damage, its co-delivery increased cleaved caspase 3 IL-1β within exacerbated OxPC-induced injury. Conversely, OxPC-mediated neurodegeneration reduced Gal3-/- Gal3+/+ neuroinflammation overexpression microglia/macrophages may be detrimental CNS.SIGNIFICANCE STATEMENT accelerates such Understanding molecular mechanisms increases susceptibility damage could strategies manage Here, highlight microglia/macrophage-associated (Gal3) More importantly, co-injection lipids found lesions, caused greater injection alone, whereas genetic loss damage. These results demonstrate suggest deposition contribute neurodegeneration.