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Water-Soluble Lynx1 Upregulates Dendritic Spine Density and Stimulates Astrocytic Network and Signaling

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Abstract

Secreted and membrane-tethered mammalian neuromodulators from the Ly6/uPAR family are involved in regulation of many physiological processes. Some of them are expressed in the CNS in the neurons of different brain regions and target neuronal membrane receptors. Thus, Lynx1 potentiates nicotinic acetylcholine receptors (nAChRs) in the brain, while others like Lypd6 and Lypd6b suppress it. However, the mechanisms underlying the regulation of cognitive processes by these neuromodulators remain unclear. Here, we showed that water-soluble analogue of Lynx1 (ws-Lynx-1) targets α7-nAChRs both in the hippocampal neurons and astrocytes. Incubation of astrocytes with ws-Lynx1 increased expression of connexins 30 and 43; α4, α5, and β4 integrins; and E- and P-cadherins. Ws-Lynx1 reduced secretion of pro-inflammatory adhesion factors ICAM-1, PSGL-1, and VCAM-1 and downregulated secretion of CD44 and NCAM, which inhibit synaptic plasticity. Moreover, increased astrocytic secretion of the dendritic growth activator ALCAM and neurogenesis regulator E-selectin was observed. Incubation of neurons with ws-Lynx1 potentiated α7-nAChRs and upregulated dendritic spine density. Thus, the pro-cognitive activity of ws-Lynx1 observed previously can be explained by stimulation of astrocytic network and signaling together with up-regulation of spinogenesis, potentiation of the α7-nAChRs, and neuronal and synaptic plasticity. For comparison, influence of water-soluble analogues of a set of Ly6/uPAR proteins (SLURP-1, SLURP-2, Lypd6, Lypd6b, and PSCA) on dendritic spine density and diameter was studied. Data obtained give new insights on the role of Ly6/uPAR proteins in the brain and open new prospects for the development of drugs to improve cognitive function.

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Data Availability

No datasets were generated or analysed during the current study.

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Acknowledgements

Mikhail Kirpichnikov and Ekaterina Lyukmanova are part of an innovative drug development team based on structural biology and bioinformatics at MSU-BIT University in Shenzhen (#2022KCXTD034).

Funding

This research was funded by Russian Science Foundation (grant number 24–14-00419).

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Authors and Affiliations

  1. Faculty of Biology, Shenzhen MSU-BIT University, Shenzhen, China

    Ekaterina Lyukmanova & Yuqi Che

  2. Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia

    Ekaterina Lyukmanova, Artem Kirichenko, Dmitry Kulbatskii, Aizek Isaev, Ilya Kukushkin, Mikhail Kirpichnikov & Maxim Bychkov

  3. Moscow Center for Advanced Studies, Moscow, Russia

    Ekaterina Lyukmanova, Artem Kirichenko, Aizek Isaev & Ilya Kukushkin

  4. Molecular Technologies of the Living Systems and Synthetic Biology, Faculty of Biology, Interdisciplinary Scientific and Educational School of Moscow University, Lomonosov Moscow State University, Moscow, Russia

    Ekaterina Lyukmanova & Mikhail Kirpichnikov

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Contributions

Conceptualization, MB, EL; Investigation, formal analysis, data curation, MB, AK, DK, AI, YC, IK; Writing—original draft preparation, MB, EL; Writing—review and editing, AK, DK, AI, MK; Visualization, MB, AK, EL; Supervision, EL, MK; Project administration, EL; Funding acquisition, EL. All authors reviewed the manuscript.

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Correspondence to Ekaterina Lyukmanova.

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The animals were kept in standard conditions of the Laboratory Animal Nursery of the IBCH RAS, having international accreditation AAALACi. All animal care and experimental procedures were performed in accordance with the guidelines set forth by the European Communities Council Directive of November 24, 1986 (86/609/EEC), directive of the European Parliament and Council European Union of September 22, 2010 (2010/63/EU) on the protection of animals used for scientific purposes. Experiments were approved by the Ethical Committee of the Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS for the control of the maintenance and use of animals (protocol #312/2020 from 18 December 2020).

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Lyukmanova, E., Kirichenko, A., Kulbatskii, D. et al. Water-Soluble Lynx1 Upregulates Dendritic Spine Density and Stimulates Astrocytic Network and Signaling. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04627-1

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