Targeting galectin-3 to counteract spike-phase uncoupling of fast-spiking interneurons to gamma oscillations in Alzheimer's disease.

Autor: Arroyo-García LE; Neuronal Oscillations Laboratory, Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 17164, Solna, Sweden., Bachiller S; Experimental Neuroinflammation Laboratory, Department of Experimental Medical Science, Lund University, BMC B11, 221 84, Lund, Sweden.; Clinical Unit of Infectious Diseases, Microbiology and Parasitology, Institute of Biomedicine of Seville (IBiS), Virgen del Rocío University Hospital, CSIC, University of Seville, Seville, Spain., Ruiz R; Department of Biochemistry and Molecular Biology, University of Seville, Calle Profesor García González Nº2, 41012, Seville, Spain., Boza-Serrano A; Experimental Neuroinflammation Laboratory, Department of Experimental Medical Science, Lund University, BMC B11, 221 84, Lund, Sweden.; Department of Biochemistry and Molecular Biology, University of Seville, Calle Profesor García González Nº2, 41012, Seville, Spain., Rodríguez-Moreno A; Laboratory of Cellular Neuroscience and Plasticity, Department of Physiology, Anatomy and Cellular Biology, Universidad Pablo de Olavide, Carretera de Utrera Km-1, 41013, Seville, Spain., Deierborg T; Experimental Neuroinflammation Laboratory, Department of Experimental Medical Science, Lund University, BMC B11, 221 84, Lund, Sweden., Andrade-Talavera Y; Neuronal Oscillations Laboratory, Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 17164, Solna, Sweden. yandtal@upo.es.; Laboratory of Cellular Neuroscience and Plasticity, Department of Physiology, Anatomy and Cellular Biology, Universidad Pablo de Olavide, Carretera de Utrera Km-1, 41013, Seville, Spain. yandtal@upo.es., Fisahn A; Neuronal Oscillations Laboratory, Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 17164, Solna, Sweden. andre.fisahn@ki.se.; Department of Biosciences and Nutrition, Neo, Karolinska Institutet, 141 83, Huddinge, Sweden. andre.fisahn@ki.se.
Jazyk: angličtina
Zdroj: Translational neurodegeneration [Transl Neurodegener] 2023 Feb 06; Vol. 12 (1), pp. 6. Date of Electronic Publication: 2023 Feb 06.
DOI: 10.1186/s40035-023-00338-0
Abstrakt: Background: Alzheimer's disease (AD) is a progressive multifaceted neurodegenerative disorder for which no disease-modifying treatment exists. Neuroinflammation is central to the pathology progression, with evidence suggesting that microglia-released galectin-3 (gal3) plays a pivotal role by amplifying neuroinflammation in AD. However, the possible involvement of gal3 in the disruption of neuronal network oscillations typical of AD remains unknown.
Methods: Here, we investigated the functional implications of gal3 signaling on experimentally induced gamma oscillations ex vivo (20-80 Hz) by performing electrophysiological recordings in the hippocampal CA3 area of wild-type (WT) mice and of the 5×FAD mouse model of AD. In addition, the recorded slices from WT mice under acute gal3 application were analyzed with RT-qPCR to detect expression of some neuroinflammation-related genes, and amyloid-β (Aβ) plaque load was quantified by immunostaining in the CA3 area of 6-month-old 5×FAD mice with or without Gal3 knockout (KO).
Results: Gal3 application decreased gamma oscillation power and rhythmicity in an activity-dependent manner, which was accompanied by impairment of cellular dynamics in fast-spiking interneurons (FSNs) and pyramidal cells. We found that the gal3-induced disruption was mediated by the gal3 carbohydrate-recognition domain and prevented by the gal3 inhibitor TD139, which also prevented Aβ42-induced degradation of gamma oscillations. Furthermore, the 5×FAD mice lacking gal3 (5×FAD-Gal3KO) exhibited WT-like gamma network dynamics and decreased Aβ plaque load.
Conclusions: We report for the first time that gal3 impairs neuronal network dynamics by spike-phase uncoupling of FSNs, inducing a network performance collapse. Moreover, our findings suggest gal3 inhibition as a potential therapeutic strategy to counteract the neuronal network instability typical of AD and other neurological disorders encompassing neuroinflammation and cognitive decline.
(© 2023. The Author(s).)
Databáze: MEDLINE
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