I2-Imidazoline Ligand CR4056 Improves Memory, Increases ApoE Expression and Reduces BBB Leakage in 5xFAD Mice
Recent evidence suggests that I2-imidazoline ligands have neuroprotective properties in animal models of neurodegeneration, such as Alzheimer’s disease (AD). We recently demonstrated that the I2-ligand BU224 reversed memory impairments in AD transgenic mice and this effect was not because of reducti...
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| Format: | Article |
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MDPI AG
2022-06-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/13/7320 |
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| author | Bibiana C. Mota Nathan Ashburner Laura Abelleira-Hervas Liyueyue Liu Robertas Aleksynas Lucio Claudio Rovati Gianfranco Caselli Magdalena Sastre |
| author_facet | Bibiana C. Mota Nathan Ashburner Laura Abelleira-Hervas Liyueyue Liu Robertas Aleksynas Lucio Claudio Rovati Gianfranco Caselli Magdalena Sastre |
| author_sort | Bibiana C. Mota |
| collection | DOAJ |
| description | Recent evidence suggests that I2-imidazoline ligands have neuroprotective properties in animal models of neurodegeneration, such as Alzheimer’s disease (AD). We recently demonstrated that the I2-ligand BU224 reversed memory impairments in AD transgenic mice and this effect was not because of reductions in amyloid-β (Aβ) deposition. In this study, our aim was to determine the therapeutic potential of the powerful analgesic I2-imidazoline ligand CR4056 in the 5xFAD model of AD, since this ligand has been proven to be safely tolerated in humans. Sub-chronic oral administration of CR4056 (30 mg/kg for 10 days) led to an improvement in recognition memory in 6-month-old 5xFAD mice, but not in wild-type littermates, without affecting Aβ levels or deposition. Our results also revealed a change in the profile of microglia by CR4056, resulting in a suppression of pro-inflammatory activated microglia, but increased the density of astrocytes and the expression of ApoE, which is mainly produced by these glial cells. In addition, CR4056 restored fibrinogen extravasation, affecting the distribution of markers of astrocytic end feet in blood vessels. Therefore, these results suggest that CR4056 protects against Aβ-mediated neuroinflammation and vascular damage, and offers therapeutic potential at any stage of AD. |
| first_indexed | 2024-03-09T21:48:01Z |
| format | Article |
| id | doaj.art-74869a88d2e141a3ab3de31cece0f493 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T21:48:01Z |
| publishDate | 2022-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-74869a88d2e141a3ab3de31cece0f4932023-11-23T20:11:51ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-06-012313732010.3390/ijms23137320I2-Imidazoline Ligand CR4056 Improves Memory, Increases ApoE Expression and Reduces BBB Leakage in 5xFAD MiceBibiana C. Mota0Nathan Ashburner1Laura Abelleira-Hervas2Liyueyue Liu3Robertas Aleksynas4Lucio Claudio Rovati5Gianfranco Caselli6Magdalena Sastre7Department of Brain Sciences, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UKDepartment of Brain Sciences, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UKDepartment of Brain Sciences, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UKDepartment of Brain Sciences, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UKDepartment of Brain Sciences, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UKRottapharm Biotech S.r.l., 20900 Monza, ItalyRottapharm Biotech S.r.l., 20900 Monza, ItalyDepartment of Brain Sciences, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UKRecent evidence suggests that I2-imidazoline ligands have neuroprotective properties in animal models of neurodegeneration, such as Alzheimer’s disease (AD). We recently demonstrated that the I2-ligand BU224 reversed memory impairments in AD transgenic mice and this effect was not because of reductions in amyloid-β (Aβ) deposition. In this study, our aim was to determine the therapeutic potential of the powerful analgesic I2-imidazoline ligand CR4056 in the 5xFAD model of AD, since this ligand has been proven to be safely tolerated in humans. Sub-chronic oral administration of CR4056 (30 mg/kg for 10 days) led to an improvement in recognition memory in 6-month-old 5xFAD mice, but not in wild-type littermates, without affecting Aβ levels or deposition. Our results also revealed a change in the profile of microglia by CR4056, resulting in a suppression of pro-inflammatory activated microglia, but increased the density of astrocytes and the expression of ApoE, which is mainly produced by these glial cells. In addition, CR4056 restored fibrinogen extravasation, affecting the distribution of markers of astrocytic end feet in blood vessels. Therefore, these results suggest that CR4056 protects against Aβ-mediated neuroinflammation and vascular damage, and offers therapeutic potential at any stage of AD.https://www.mdpi.com/1422-0067/23/13/7320imidazolineastrocyteAlzheimer’s diseaseamyloid-βblood–brain barrieraquaporin-4 |
| spellingShingle | Bibiana C. Mota Nathan Ashburner Laura Abelleira-Hervas Liyueyue Liu Robertas Aleksynas Lucio Claudio Rovati Gianfranco Caselli Magdalena Sastre I2-Imidazoline Ligand CR4056 Improves Memory, Increases ApoE Expression and Reduces BBB Leakage in 5xFAD Mice International Journal of Molecular Sciences imidazoline astrocyte Alzheimer’s disease amyloid-β blood–brain barrier aquaporin-4 |
| title | I2-Imidazoline Ligand CR4056 Improves Memory, Increases ApoE Expression and Reduces BBB Leakage in 5xFAD Mice |
| title_full | I2-Imidazoline Ligand CR4056 Improves Memory, Increases ApoE Expression and Reduces BBB Leakage in 5xFAD Mice |
| title_fullStr | I2-Imidazoline Ligand CR4056 Improves Memory, Increases ApoE Expression and Reduces BBB Leakage in 5xFAD Mice |
| title_full_unstemmed | I2-Imidazoline Ligand CR4056 Improves Memory, Increases ApoE Expression and Reduces BBB Leakage in 5xFAD Mice |
| title_short | I2-Imidazoline Ligand CR4056 Improves Memory, Increases ApoE Expression and Reduces BBB Leakage in 5xFAD Mice |
| title_sort | i2 imidazoline ligand cr4056 improves memory increases apoe expression and reduces bbb leakage in 5xfad mice |
| topic | imidazoline astrocyte Alzheimer’s disease amyloid-β blood–brain barrier aquaporin-4 |
| url | https://www.mdpi.com/1422-0067/23/13/7320 |
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