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ORIGINAL RESEARCH article

Front. Neurosci.
Sec. Neurodegeneration
Volume 18 - 2024 | doi: 10.3389/fnins.2024.1504765
This article is part of the Research Topic Myeloid Cells as Active Players in Human Neurodegenerative Diseases View all 4 articles

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

Provisionally accepted
Tawfik Abou Assale Tawfik Abou Assale Negin Afrang Negin Afrang Jannis Wißfeld Jannis Wißfeld German Cuevas-Rios German Cuevas-Rios Christine Klaus Christine Klaus Bettina Linnartz-Gerlach Bettina Linnartz-Gerlach Harald Neumann Harald Neumann *
  • Medical Faculty and University Hospital of Bonn, University of Bonn, Bonn, Germany

The final, formatted version of the article will be published soon.

    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 α-2-8-linked oligo-/polysialylated glycomolecules with inhibitory effects on the microglial inflammatory pathways. Recently, the SIGLEC11 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 pars compacta 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 tumor necrosis factor alpha (Tnf-alpha and interleukin 1 beta (Il-1beta as well as the oxidative stress markers cytochrome b-245 alpha and beta (Cyba and Cybb) and the nitric oxide synthase 2 (Nos2), 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 (C3, C4, and Itgam), along with the complement C1q subcomponents a-c (C1qa, C1qb, and C1qc). 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.

    Keywords: Siglec-11, Aging, Microglia, neurodegeneration, Neuroinflammation, Oxidative Stress

    Received: 01 Oct 2024; Accepted: 02 Dec 2024.

    Copyright: © 2024 Abou Assale, Afrang, Wißfeld, Cuevas-Rios, Klaus, Linnartz-Gerlach and Neumann. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Harald Neumann, Medical Faculty and University Hospital of Bonn, University of Bonn, Bonn, Germany

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