Anti-Inflammatory Treatment with FTY720 Starting after Onset of Symptoms Reverses Synaptic Deficits in an AD Mouse Model
Therapeutic approaches providing effective medication for Alzheimer’s disease (AD) patients after disease onset are urgently needed. Previous studies in AD mouse models suggested that physical exercise or changed lifestyle can delay AD-related synaptic and memory dysfunctions when treatment started...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/23/8957 |
| _version_ | 1797546748078456832 |
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| author | Georgia-Ioanna Kartalou Ana Rita Salgueiro-Pereira Thomas Endres Angelina Lesnikova Plinio Casarotto Paula Pousinha Kevin Delanoe Elke Edelmann Eero Castrén Kurt Gottmann Hélène Marie Volkmar Lessmann |
| author_facet | Georgia-Ioanna Kartalou Ana Rita Salgueiro-Pereira Thomas Endres Angelina Lesnikova Plinio Casarotto Paula Pousinha Kevin Delanoe Elke Edelmann Eero Castrén Kurt Gottmann Hélène Marie Volkmar Lessmann |
| author_sort | Georgia-Ioanna Kartalou |
| collection | DOAJ |
| description | Therapeutic approaches providing effective medication for Alzheimer’s disease (AD) patients after disease onset are urgently needed. Previous studies in AD mouse models suggested that physical exercise or changed lifestyle can delay AD-related synaptic and memory dysfunctions when treatment started in juvenile animals long before onset of disease symptoms, while a pharmacological treatment that can reverse synaptic and memory deficits in AD mice was thus far not identified. Repurposing food and drug administration (FDA)-approved drugs for treatment of AD is a promising way to reduce the time to bring such medication into clinical practice. The sphingosine-1 phosphate analog fingolimod (FTY720) was approved recently for treatment of multiple sclerosis patients. Here, we addressed whether fingolimod rescues AD-related synaptic deficits and memory dysfunction in an amyloid precursor protein/presenilin-1 (APP/PS1) AD mouse model when medication starts after onset of symptoms (at five months). Male mice received intraperitoneal injections of fingolimod for one to two months starting at five to six months. This treatment rescued spine density as well as long-term potentiation in hippocampal cornu ammonis-1 (CA1) pyramidal neurons, that were both impaired in untreated APP/PS1 animals at six to seven months of age. Immunohistochemical analysis with markers of microgliosis (ionized calcium-binding adapter molecule 1; Iba1) and astrogliosis (glial fibrillary acid protein; GFAP) revealed that our fingolimod treatment regime strongly down regulated neuroinflammation in the hippocampus and neocortex of this AD model. These effects were accompanied by a moderate reduction of Aβ accumulation in hippocampus and neocortex. Our results suggest that fingolimod, when applied after onset of disease symptoms in an APP/PS1 mouse model, rescues synaptic pathology that is believed to underlie memory deficits in AD mice, and that this beneficial effect is mediated via anti-neuroinflammatory actions of the drug on microglia and astrocytes. |
| first_indexed | 2024-03-10T14:34:36Z |
| format | Article |
| id | doaj.art-0b66fe9c2ad341a78d6a37042b170cda |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T14:34:36Z |
| publishDate | 2020-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-0b66fe9c2ad341a78d6a37042b170cda2023-11-20T22:18:19ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-11-012123895710.3390/ijms21238957Anti-Inflammatory Treatment with FTY720 Starting after Onset of Symptoms Reverses Synaptic Deficits in an AD Mouse ModelGeorgia-Ioanna Kartalou0Ana Rita Salgueiro-Pereira1Thomas Endres2Angelina Lesnikova3Plinio Casarotto4Paula Pousinha5Kevin Delanoe6Elke Edelmann7Eero Castrén8Kurt Gottmann9Hélène Marie10Volkmar Lessmann11Institute of Physiology, Medical Faculty, Otto-von-Guericke University, 39120 Magdeburg, GermanyUniversité Côte d’Azur, CNRS, IPMC, UMR7275, 06560 Valbonne, FranceInstitute of Physiology, Medical Faculty, Otto-von-Guericke University, 39120 Magdeburg, GermanyNeuroscience Center, HiLIFE, University of Helsinki, 00290 Helsinki, FinlandNeuroscience Center, HiLIFE, University of Helsinki, 00290 Helsinki, FinlandUniversité Côte d’Azur, CNRS, IPMC, UMR7275, 06560 Valbonne, FranceUniversité Côte d’Azur, CNRS, IPMC, UMR7275, 06560 Valbonne, FranceInstitute of Physiology, Medical Faculty, Otto-von-Guericke University, 39120 Magdeburg, GermanyNeuroscience Center, HiLIFE, University of Helsinki, 00290 Helsinki, FinlandInstitute of Neuro- and Sensory Physiology, Medical Faculty, Heinrich Heine University, 40225 Duesseldorf, GermanyUniversité Côte d’Azur, CNRS, IPMC, UMR7275, 06560 Valbonne, FranceInstitute of Physiology, Medical Faculty, Otto-von-Guericke University, 39120 Magdeburg, GermanyTherapeutic approaches providing effective medication for Alzheimer’s disease (AD) patients after disease onset are urgently needed. Previous studies in AD mouse models suggested that physical exercise or changed lifestyle can delay AD-related synaptic and memory dysfunctions when treatment started in juvenile animals long before onset of disease symptoms, while a pharmacological treatment that can reverse synaptic and memory deficits in AD mice was thus far not identified. Repurposing food and drug administration (FDA)-approved drugs for treatment of AD is a promising way to reduce the time to bring such medication into clinical practice. The sphingosine-1 phosphate analog fingolimod (FTY720) was approved recently for treatment of multiple sclerosis patients. Here, we addressed whether fingolimod rescues AD-related synaptic deficits and memory dysfunction in an amyloid precursor protein/presenilin-1 (APP/PS1) AD mouse model when medication starts after onset of symptoms (at five months). Male mice received intraperitoneal injections of fingolimod for one to two months starting at five to six months. This treatment rescued spine density as well as long-term potentiation in hippocampal cornu ammonis-1 (CA1) pyramidal neurons, that were both impaired in untreated APP/PS1 animals at six to seven months of age. Immunohistochemical analysis with markers of microgliosis (ionized calcium-binding adapter molecule 1; Iba1) and astrogliosis (glial fibrillary acid protein; GFAP) revealed that our fingolimod treatment regime strongly down regulated neuroinflammation in the hippocampus and neocortex of this AD model. These effects were accompanied by a moderate reduction of Aβ accumulation in hippocampus and neocortex. Our results suggest that fingolimod, when applied after onset of disease symptoms in an APP/PS1 mouse model, rescues synaptic pathology that is believed to underlie memory deficits in AD mice, and that this beneficial effect is mediated via anti-neuroinflammatory actions of the drug on microglia and astrocytes.https://www.mdpi.com/1422-0067/21/23/8957Alzheimer’s diseasefingolimodFTY720APP/PS1spineslong-term potentiation |
| spellingShingle | Georgia-Ioanna Kartalou Ana Rita Salgueiro-Pereira Thomas Endres Angelina Lesnikova Plinio Casarotto Paula Pousinha Kevin Delanoe Elke Edelmann Eero Castrén Kurt Gottmann Hélène Marie Volkmar Lessmann Anti-Inflammatory Treatment with FTY720 Starting after Onset of Symptoms Reverses Synaptic Deficits in an AD Mouse Model International Journal of Molecular Sciences Alzheimer’s disease fingolimod FTY720 APP/PS1 spines long-term potentiation |
| title | Anti-Inflammatory Treatment with FTY720 Starting after Onset of Symptoms Reverses Synaptic Deficits in an AD Mouse Model |
| title_full | Anti-Inflammatory Treatment with FTY720 Starting after Onset of Symptoms Reverses Synaptic Deficits in an AD Mouse Model |
| title_fullStr | Anti-Inflammatory Treatment with FTY720 Starting after Onset of Symptoms Reverses Synaptic Deficits in an AD Mouse Model |
| title_full_unstemmed | Anti-Inflammatory Treatment with FTY720 Starting after Onset of Symptoms Reverses Synaptic Deficits in an AD Mouse Model |
| title_short | Anti-Inflammatory Treatment with FTY720 Starting after Onset of Symptoms Reverses Synaptic Deficits in an AD Mouse Model |
| title_sort | anti inflammatory treatment with fty720 starting after onset of symptoms reverses synaptic deficits in an ad mouse model |
| topic | Alzheimer’s disease fingolimod FTY720 APP/PS1 spines long-term potentiation |
| url | https://www.mdpi.com/1422-0067/21/23/8957 |
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