Neuroprotective role of sialic-acid-binding immunoglobulin-like lectin-11 in humanized transgenic mice

Brain aging is a chronic process linked to inflammation, microglial activation, and oxidative damage, which can ultimately lead to neuronal loss. Sialic acid-binding immunoglobulin-like lectin-11 (SIGLEC-11) is a human lineage-specific microglial cell surface receptor that recognizes <i>α</i>-2-8-linked oligo-/polysialylated glycomolecules with inhibitory effects on the microglial inflammatory pathways. Recently, the <i>SIGLEC11</i> gene locus was prioritized as a top tier microglial gene with potential causality to Alzheimer's disease, although its role in inflammation and neurodegeneration remains poorly understood. In this study, aged Siglec-11 transgenic (tg) mice, which expressed the human SIGLEC-11 receptor on microglia and tissue macrophages, were investigated. The brains of the Siglec-11 tg mice were analyzed in 6-month-old mature mice and 24-month-old aged mice using immunohistochemistry and transcriptomics. Results showed decreased density and fewer clusters of ionized calcium binding adaptor molecule 1 (Iba1)-positive microglial cells in the hippocampus and substantia nigra, as well as less lipid-laden microglia in the Siglec-11 tg in comparison to wildtype (WT) controls. Additionally, Siglec-11 tg mice exhibited less age-related neuronal loss in the substantia nigra <i>pars compacta</i> in comparison to WT mice. Transcriptome analysis revealed suppression of oxidative phosphorylation and inflammatory pathways in Siglec-11 tg brains at 6 months, with further suppression of complement and coagulation cascades at 24 months of age in comparison to WT mice. Gene transcript levels of the pro-inflammatory cytokines <i>tumor necrosis factor alpha</i> (<i>Tnf</i>) and <i>interleukin 1 beta</i> (<i>Il-1β</i>) as well as the oxidative stress markers <i>cytochrome b-245 alpha</i> and <i>beta</i> (<i>Cyba</i> and <i>Cybb</i>) and the nitric oxide synthase 2 (<i>Nos2</i>), were reduced in the brains of 24-month-old Siglec-11 tg mice relative to WT controls. Brains of 24-month-old Siglec-11 tg mice also exhibited lower gene transcription of complement components 3, 4, and integrin alpha M (<i>C3, C4,</i> and <i>Itgam</i>), along with the complement C1q subcomponents a-c (<i>C1qa, C1qb</i>, and <i>C1qc</i>). In summary, aged Siglec-11 tg mice displayed reduced brain inflammation and oxidative stress, as well as protection against age-related neuronal loss in the substantia nigra.