Glial Gap Junction Pathology in the Spinal Cord of the 5xFAD Mouse Model of Early-Onset Alzheimer’s Disease
Gap junctions (GJs) are specialized transmembrane channels assembled by two hemi-channels of six connexin (Cx) proteins that facilitate neuroglial crosstalk in the central nervous system (CNS). Previous studies confirmed the crucial role of glial GJs in neurodegenerative disorders with dementia or m...
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MDPI AG
2022-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/24/15597 |
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| author | Maria Pechlivanidou Ioanna Kousiappa Stella Angeli Irene Sargiannidou Andreas M. Koupparis Savvas S. Papacostas Kleopas A. Kleopa |
| author_facet | Maria Pechlivanidou Ioanna Kousiappa Stella Angeli Irene Sargiannidou Andreas M. Koupparis Savvas S. Papacostas Kleopas A. Kleopa |
| author_sort | Maria Pechlivanidou |
| collection | DOAJ |
| description | Gap junctions (GJs) are specialized transmembrane channels assembled by two hemi-channels of six connexin (Cx) proteins that facilitate neuroglial crosstalk in the central nervous system (CNS). Previous studies confirmed the crucial role of glial GJs in neurodegenerative disorders with dementia or motor dysfunction including Alzheimer’s disease (AD). The aim of this study was to examine the alterations in astrocyte and related oligodendrocyte GJs in association with Aβ plaques in the spinal cord of the 5xFAD mouse model of AD. Our analysis revealed abundant Aβ plaque deposition, activated microglia, and astrogliosis in 12-month-old (12M) 5xFAD mice, with significant impairment of motor performance starting from 3-months (3M) of age. Additionally, 12M 5xFAD mice displayed increased immunoreactivity of astroglial Cx43 and Cx30 surrounding Aβ plaques and higher protein levels, indicating upregulated astrocyte-to-astrocyte GJ connectivity. In addition, they demonstrated increased numbers of mature CC1-positive and precursor oligodendrocytes (OPCs) with higher immunoreactivity of Cx47-positive GJs in individual cells. Moreover, total Cx47 protein levels were significantly elevated in 12M 5xFAD, reflecting increased oligodendrocyte-to-oligodendrocyte Cx47–Cx47 GJ connectivity. In contrast, we observed a marked reduction in Cx32 protein levels in 12M 5xFAD spinal cords compared with controls, while qRT-PCR analysis revealed a significant upregulation in <i>Cx32</i> mRNA levels. Finally, myelin deficits were found focally in the areas occupied by Aβ plaques, whereas axons themselves remained preserved. Overall, our data provide novel insights into the altered glial GJ expression in the spinal cord of the 5xFAD model of AD and the implicated role of GJ pathology in neurodegeneration. Further investigation to understand the functional consequences of these extensive alterations in oligodendrocyte–astrocyte (O/A) GJ connectivity is warranted. |
| first_indexed | 2024-03-09T16:20:05Z |
| format | Article |
| id | doaj.art-cf5c1bbc2d094e2e84691252d25988b8 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T16:20:05Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-cf5c1bbc2d094e2e84691252d25988b82023-11-24T15:24:17ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-12-0123241559710.3390/ijms232415597Glial Gap Junction Pathology in the Spinal Cord of the 5xFAD Mouse Model of Early-Onset Alzheimer’s DiseaseMaria Pechlivanidou0Ioanna Kousiappa1Stella Angeli2Irene Sargiannidou3Andreas M. Koupparis4Savvas S. Papacostas5Kleopas A. Kleopa6Neurobiology Department, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, CyprusNeurobiology Department, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, CyprusMedical School, University of Nicosia, Nicosia 2414, CyprusNeuroscience Department, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, CyprusNeurobiology Department, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, CyprusNeurobiology Department, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, CyprusNeuroscience Department, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, CyprusGap junctions (GJs) are specialized transmembrane channels assembled by two hemi-channels of six connexin (Cx) proteins that facilitate neuroglial crosstalk in the central nervous system (CNS). Previous studies confirmed the crucial role of glial GJs in neurodegenerative disorders with dementia or motor dysfunction including Alzheimer’s disease (AD). The aim of this study was to examine the alterations in astrocyte and related oligodendrocyte GJs in association with Aβ plaques in the spinal cord of the 5xFAD mouse model of AD. Our analysis revealed abundant Aβ plaque deposition, activated microglia, and astrogliosis in 12-month-old (12M) 5xFAD mice, with significant impairment of motor performance starting from 3-months (3M) of age. Additionally, 12M 5xFAD mice displayed increased immunoreactivity of astroglial Cx43 and Cx30 surrounding Aβ plaques and higher protein levels, indicating upregulated astrocyte-to-astrocyte GJ connectivity. In addition, they demonstrated increased numbers of mature CC1-positive and precursor oligodendrocytes (OPCs) with higher immunoreactivity of Cx47-positive GJs in individual cells. Moreover, total Cx47 protein levels were significantly elevated in 12M 5xFAD, reflecting increased oligodendrocyte-to-oligodendrocyte Cx47–Cx47 GJ connectivity. In contrast, we observed a marked reduction in Cx32 protein levels in 12M 5xFAD spinal cords compared with controls, while qRT-PCR analysis revealed a significant upregulation in <i>Cx32</i> mRNA levels. Finally, myelin deficits were found focally in the areas occupied by Aβ plaques, whereas axons themselves remained preserved. Overall, our data provide novel insights into the altered glial GJ expression in the spinal cord of the 5xFAD model of AD and the implicated role of GJ pathology in neurodegeneration. Further investigation to understand the functional consequences of these extensive alterations in oligodendrocyte–astrocyte (O/A) GJ connectivity is warranted.https://www.mdpi.com/1422-0067/23/24/15597Alzheimer’s diseasegap junctionsneurodegeneration5xFADspinal cordmotor deficits |
| spellingShingle | Maria Pechlivanidou Ioanna Kousiappa Stella Angeli Irene Sargiannidou Andreas M. Koupparis Savvas S. Papacostas Kleopas A. Kleopa Glial Gap Junction Pathology in the Spinal Cord of the 5xFAD Mouse Model of Early-Onset Alzheimer’s Disease International Journal of Molecular Sciences Alzheimer’s disease gap junctions neurodegeneration 5xFAD spinal cord motor deficits |
| title | Glial Gap Junction Pathology in the Spinal Cord of the 5xFAD Mouse Model of Early-Onset Alzheimer’s Disease |
| title_full | Glial Gap Junction Pathology in the Spinal Cord of the 5xFAD Mouse Model of Early-Onset Alzheimer’s Disease |
| title_fullStr | Glial Gap Junction Pathology in the Spinal Cord of the 5xFAD Mouse Model of Early-Onset Alzheimer’s Disease |
| title_full_unstemmed | Glial Gap Junction Pathology in the Spinal Cord of the 5xFAD Mouse Model of Early-Onset Alzheimer’s Disease |
| title_short | Glial Gap Junction Pathology in the Spinal Cord of the 5xFAD Mouse Model of Early-Onset Alzheimer’s Disease |
| title_sort | glial gap junction pathology in the spinal cord of the 5xfad mouse model of early onset alzheimer s disease |
| topic | Alzheimer’s disease gap junctions neurodegeneration 5xFAD spinal cord motor deficits |
| url | https://www.mdpi.com/1422-0067/23/24/15597 |
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