The complex phenotype and function of spinal cord microglia during ALS progression and the impact of metabotropic glutamate receptor type 5 down-regulation in SOD1G93A mice
Over the last few decades, scientists' attention has shifted from neuronal to non-neuronal cells to explain the mechanisms at the basis of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). ALS is a multifactorial and multicellular disease in which microglia have a cent...
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Elsevier
2025-09-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996125002335 |
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| author | Matilde Balbi Carola Torazza Tiziana Altosole Silvia Ravera Emanuele Farinini Sara Tessitore Francesca Bacchetti Francesca Rosso Ilaria Musante Silvana Alfei Maria Cerminara Aldamaria Puliti Gilberto Filaci Daniela Fenoglio Riccardo Leardi Ernesto Fedele Giambattista Bonanno Marco Milanese Tiziana Bonifacino |
| author_facet | Matilde Balbi Carola Torazza Tiziana Altosole Silvia Ravera Emanuele Farinini Sara Tessitore Francesca Bacchetti Francesca Rosso Ilaria Musante Silvana Alfei Maria Cerminara Aldamaria Puliti Gilberto Filaci Daniela Fenoglio Riccardo Leardi Ernesto Fedele Giambattista Bonanno Marco Milanese Tiziana Bonifacino |
| author_sort | Matilde Balbi |
| collection | DOAJ |
| description | Over the last few decades, scientists' attention has shifted from neuronal to non-neuronal cells to explain the mechanisms at the basis of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). ALS is a multifactorial and multicellular disease in which microglia have a central role, during disease progression. We previously demonstrated that metabotropic glutamate receptor 5 (mGluR5) is dysfunctional in the spinal cord of the SOD1G93A ALS mice, and its in-vivo genetic or pharmacological dampening ameliorates disease outcome and astrocyte and microglia reactivity. Here, we studied the expression of typical phenotype-related markers during the disease progression in spinal cord microglia cells acutely isolated from early asymptomatic and late symptomatic SOD1G93A ALS mice. Moreover, we investigated whether reducing mGluR5 affected the microglia phenotype and function. In contrast to what we previously observed in astrocytes, mGluR5 expression decreased during disease progression in microglia acutely isolated from adult SOD1G93A mice. In-vivo genetic mGluR5 downregulation did not affect microglia phenotype-relevant markers, which evidenced a unique expression distribution. Conversely, mGluR5 reduction ameliorated redox balance and bioenergetics of adult microglia. Microglia cultured from the spinal cord of SOD1G93A pups showed that in-vitro mGluR5 pharmacological manipulation by the negative allosteric modulator CTEP partially modified their bioenergetic and oxidative status. Overall, our results suggest that mGluR5 manipulation ameliorates microglia phenotype and function in ALS by both direct and indirect mechanisms. Consequently, we hypothesised that the improvement of microglia reactive status by in-vivo mGluR5 downregulation or CTEP pharmacological modulation is supported by ameliorated bioenergetic metabolism, and the indirect astrocyte's phenotype change that promotes an improvement of the surrounding environment. |
| format | Article |
| id | doaj-art-80ef77da4a2f4fd9b87cceded3bdcb84 |
| institution | DOAJ |
| issn | 1095-953X |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj-art-80ef77da4a2f4fd9b87cceded3bdcb842025-08-20T02:45:42ZengElsevierNeurobiology of Disease1095-953X2025-09-0121310701710.1016/j.nbd.2025.107017The complex phenotype and function of spinal cord microglia during ALS progression and the impact of metabotropic glutamate receptor type 5 down-regulation in SOD1G93A miceMatilde Balbi0Carola Torazza1Tiziana Altosole2Silvia Ravera3Emanuele Farinini4Sara Tessitore5Francesca Bacchetti6Francesca Rosso7Ilaria Musante8Silvana Alfei9Maria Cerminara10Aldamaria Puliti11Gilberto Filaci12Daniela Fenoglio13Riccardo Leardi14Ernesto Fedele15Giambattista Bonanno16Marco Milanese17Tiziana Bonifacino18Department of Pharmacy (DIFAR), University of Genoa, Viale Cembrano 4, I-16148 Genova, Italy; Department of Experimental Medicine (DIMES), University of Genova, Via Alberti L.B. 2, 16132 Genova, ItalyDepartment of Pharmacy (DIFAR), University of Genoa, Viale Cembrano 4, I-16148 Genova, ItalyIRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genova, ItalyDepartment of Experimental Medicine (DIMES), University of Genova, Via Alberti L.B. 2, 16132 Genova, Italy; IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genova, ItalyDepartment of Pharmacy (DIFAR), University of Genoa, Viale Cembrano 4, I-16148 Genova, ItalyDepartment of Pharmacy (DIFAR), University of Genoa, Viale Cembrano 4, I-16148 Genova, ItalyDepartment of Pharmacy (DIFAR), University of Genoa, Viale Cembrano 4, I-16148 Genova, ItalyDepartment of Pharmacy (DIFAR), University of Genoa, Viale Cembrano 4, I-16148 Genova, ItalyDepartment of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Largo Paolo Daneo, 3, 16132 Genova, ItalyDepartment of Pharmacy (DIFAR), University of Genoa, Viale Cembrano 4, I-16148 Genova, ItalyUOC Genetica Medica, IRCCS Istituto Giannina Gaslini, Via Gerolamo Gaslini, 5, 16147, Genova, ItalyUOC Genetica Medica, IRCCS Istituto Giannina Gaslini, Via Gerolamo Gaslini, 5, 16147, Genova, Italy; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Largo Paolo Daneo, 3, 16132 Genova, ItalyIRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genova, Italy; Department of Internal Medicine, University of Genova, Viale Benedetto XV, 6, 16132 Genova, ItalyIRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genova, Italy; Department of Internal Medicine, University of Genova, Viale Benedetto XV, 6, 16132 Genova, ItalyDepartment of Pharmacy (DIFAR), University of Genoa, Viale Cembrano 4, I-16148 Genova, ItalyDepartment of Pharmacy (DIFAR), University of Genoa, Viale Cembrano 4, I-16148 Genova, ItalyDepartment of Pharmacy (DIFAR), University of Genoa, Viale Cembrano 4, I-16148 Genova, ItalyDepartment of Pharmacy (DIFAR), University of Genoa, Viale Cembrano 4, I-16148 Genova, Italy; IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genova, Italy; Corresponding author at: Department of Pharmacy (DIFAR), University of Genoa, Viale Cembrano 4, I-16148 Genova, Italy.Department of Pharmacy (DIFAR), University of Genoa, Viale Cembrano 4, I-16148 Genova, ItalyOver the last few decades, scientists' attention has shifted from neuronal to non-neuronal cells to explain the mechanisms at the basis of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). ALS is a multifactorial and multicellular disease in which microglia have a central role, during disease progression. We previously demonstrated that metabotropic glutamate receptor 5 (mGluR5) is dysfunctional in the spinal cord of the SOD1G93A ALS mice, and its in-vivo genetic or pharmacological dampening ameliorates disease outcome and astrocyte and microglia reactivity. Here, we studied the expression of typical phenotype-related markers during the disease progression in spinal cord microglia cells acutely isolated from early asymptomatic and late symptomatic SOD1G93A ALS mice. Moreover, we investigated whether reducing mGluR5 affected the microglia phenotype and function. In contrast to what we previously observed in astrocytes, mGluR5 expression decreased during disease progression in microglia acutely isolated from adult SOD1G93A mice. In-vivo genetic mGluR5 downregulation did not affect microglia phenotype-relevant markers, which evidenced a unique expression distribution. Conversely, mGluR5 reduction ameliorated redox balance and bioenergetics of adult microglia. Microglia cultured from the spinal cord of SOD1G93A pups showed that in-vitro mGluR5 pharmacological manipulation by the negative allosteric modulator CTEP partially modified their bioenergetic and oxidative status. Overall, our results suggest that mGluR5 manipulation ameliorates microglia phenotype and function in ALS by both direct and indirect mechanisms. Consequently, we hypothesised that the improvement of microglia reactive status by in-vivo mGluR5 downregulation or CTEP pharmacological modulation is supported by ameliorated bioenergetic metabolism, and the indirect astrocyte's phenotype change that promotes an improvement of the surrounding environment.http://www.sciencedirect.com/science/article/pii/S0969996125002335Amyotrophic lateral sclerosisMicrogliaAstrocytesMetabotropic glutamate receptor 5SOD1G93ANegative allosteric modulator |
| spellingShingle | Matilde Balbi Carola Torazza Tiziana Altosole Silvia Ravera Emanuele Farinini Sara Tessitore Francesca Bacchetti Francesca Rosso Ilaria Musante Silvana Alfei Maria Cerminara Aldamaria Puliti Gilberto Filaci Daniela Fenoglio Riccardo Leardi Ernesto Fedele Giambattista Bonanno Marco Milanese Tiziana Bonifacino The complex phenotype and function of spinal cord microglia during ALS progression and the impact of metabotropic glutamate receptor type 5 down-regulation in SOD1G93A mice Neurobiology of Disease Amyotrophic lateral sclerosis Microglia Astrocytes Metabotropic glutamate receptor 5 SOD1G93A Negative allosteric modulator |
| title | The complex phenotype and function of spinal cord microglia during ALS progression and the impact of metabotropic glutamate receptor type 5 down-regulation in SOD1G93A mice |
| title_full | The complex phenotype and function of spinal cord microglia during ALS progression and the impact of metabotropic glutamate receptor type 5 down-regulation in SOD1G93A mice |
| title_fullStr | The complex phenotype and function of spinal cord microglia during ALS progression and the impact of metabotropic glutamate receptor type 5 down-regulation in SOD1G93A mice |
| title_full_unstemmed | The complex phenotype and function of spinal cord microglia during ALS progression and the impact of metabotropic glutamate receptor type 5 down-regulation in SOD1G93A mice |
| title_short | The complex phenotype and function of spinal cord microglia during ALS progression and the impact of metabotropic glutamate receptor type 5 down-regulation in SOD1G93A mice |
| title_sort | complex phenotype and function of spinal cord microglia during als progression and the impact of metabotropic glutamate receptor type 5 down regulation in sod1g93a mice |
| topic | Amyotrophic lateral sclerosis Microglia Astrocytes Metabotropic glutamate receptor 5 SOD1G93A Negative allosteric modulator |
| url | http://www.sciencedirect.com/science/article/pii/S0969996125002335 |
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