Arroyo García, Luis EnriqueBachiller Sanchez Arevalo, SaraRuiz, RocíoBoza Serrano, AntonioRodríguez-Moreno, AntonioDeierborg, TomasAndrade Talavera, YunieskyFisahn, André2025-04-032025-04-032023Arroyo-García LE, Bachiller S, Ruiz R, Boza-Serrano A, Rodríguez-Moreno A, Deierborg T, Andrade-Talavera Y, Fisahn A. Targeting galectin-3 to counteract spike-phase uncoupling of fast-spiking interneurons to gamma oscillations in Alzheimer's disease. Transl Neurodegener. 2023 Feb 6;12(1):6. doi: 10.1186/s40035-023-00338-0.10.1186/s40035-023-00338-0https://hdl.handle.net/10433/23718Background: 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.application/pdfenAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/Galectin‑3Gamma oscillationsNeuronal network dynamicsFast‑spiking interneuronsAlzheimer’s disease modelsNeuroinflammationTD139Hippocampusjournal articleopen access