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

作　　者：Luis Enrique Arroyo-García Sara Bachiller Rocío Ruiz Antonio Boza-Serrano Antonio Rodríguez-Moreno Tomas Deierborg Yuniesky Andrade-Talavera AndréFisahn 

机构地区：[1]Neuronal Oscillations Laboratory,Division of Neurogeriatrics,Center for Alzheimer Research,Department of Neurobiology,Care Sciences and Society,Karolinska Institutet,17164 Solna,Sweden [2]Experimental Neuroinflammation Laboratory,Department of Experimental Medical Science,Lund University,BMC B11,22184 Lund,Sweden [3]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 [4]Department of Biochemistry and Molecular Biology,University of Seville,Calle Profesor García González Nº2,41012 Seville,Spain [5]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 [6]Department of Biosciences and Nutrition,Neo,Karolinska Institutet,14183 Huddinge,Sweden

出　　处：《Translational Neurodegeneration》2023年第1期801-823,共23页转化神经变性病（英文）

基　　金：funding provided by Karolinska Institute.This work was supported by the Swedish Research Council,the Swedish Brain Foundation,the Swedish Alzheimer Foundation,theÅhlén Foundation(AF),the Berger Foundation(TD),the Olle Engkvist Foundation(TD),G&K Kock Foundation(TD),the Strategic Research Area MultiPark at Lund University(TD),the Foundation for Geriatric Diseases at Karolinska Institutet,theÅhlén Foundation(YAT),Consejo Nacional de Ciencia y Tecnología(CONACYT)postdoctoral fellowships and StratNeuro program at Karolinska Institutet(LEAG),Lindhés Advokabyra AB Grant and Stohnes Stiftelse(LEAG,YAT);the Spanish Ministerio de Ciencia e Innovación(MICIN/AEI/FEDER:PID2019-107677 GB-I00,ARM).

摘　　要：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.Further-more,the 5×FAD mice lacking gal3(5×FAD-Gal3KO)exhibited WT-like gamma network dynamics and decreased Aβplaque 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.

关 键 词：GALECTIN-3 Gamma oscillations Neuronal network dynamics Fast-spiking interneurons Alzheimer’s disease models Neuroinflammation TD139 Hippocampus 

分 类 号：R749.16[医药卫生—神经病学与精神病学]