Positive Allosteric Modulators of SERCA Pump Restore Dendritic Spines and Rescue Long-Term Potentiation Defects in Alzheimer’s Disease Mouse Model
Alzheimer’s disease (AD) is a neurodegenerative disorder that affects memory formation and storage processes. Dysregulated neuronal calcium (Ca<sup>2+</sup>) has been identified as one of the key pathogenic events in AD, and it has been suggested that pharmacological agents that stabiliz...
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MDPI AG
2023-09-01
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| Series: | International Journal of Molecular Sciences |
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| author | Anastasiya Rakovskaya Alexander Erofeev Egor Vinokurov Ekaterina Pchitskaya Russell Dahl Ilya Bezprozvanny |
| author_facet | Anastasiya Rakovskaya Alexander Erofeev Egor Vinokurov Ekaterina Pchitskaya Russell Dahl Ilya Bezprozvanny |
| author_sort | Anastasiya Rakovskaya |
| collection | DOAJ |
| description | Alzheimer’s disease (AD) is a neurodegenerative disorder that affects memory formation and storage processes. Dysregulated neuronal calcium (Ca<sup>2+</sup>) has been identified as one of the key pathogenic events in AD, and it has been suggested that pharmacological agents that stabilize Ca<sup>2+</sup> neuronal signaling can act as disease-modifying agents in AD. In previous studies, we demonstrated that positive allosteric regulators (PAMs) of the sarco/endoplasmic reticulum Ca<sup>2+</sup> ATPase (SERCA) pump might act as such Ca<sup>2+</sup>-stabilizing agents and exhibit neuroprotective properties. In the present study, we evaluated effects of a set of novel SERCA PAM agents on the rate of Ca<sup>2+</sup> extraction from the cytoplasm of the HEK293T cell line, on morphometric parameters of dendritic spines of primary hippocampal neurons in normal conditions and in conditions of amyloid toxicity, and on long-term potentiation in slices derived from 5xFAD transgenic mice modeling AD. Several SERCA PAM compounds demonstrated neuroprotective properties, and the compound NDC-9009 showed the best results. The findings in this study support the hypothesis that the SERCA pump is a potential therapeutic target for AD treatment and that NDC-9009 is a promising lead molecule to be used in the development of disease-modifying agents for AD. |
| first_indexed | 2024-03-10T22:40:25Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T22:40:25Z |
| publishDate | 2023-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-875f9eda02374e45b3661e30ba68cdff2023-11-19T11:05:58ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-09-0124181397310.3390/ijms241813973Positive Allosteric Modulators of SERCA Pump Restore Dendritic Spines and Rescue Long-Term Potentiation Defects in Alzheimer’s Disease Mouse ModelAnastasiya Rakovskaya0Alexander Erofeev1Egor Vinokurov2Ekaterina Pchitskaya3Russell Dahl4Ilya Bezprozvanny5Laboratory of Molecular Neurodegeneration, Peter the Great St. Petersburg Polytechnical University, St. Petersburg 195251, RussiaLaboratory of Molecular Neurodegeneration, Peter the Great St. Petersburg Polytechnical University, St. Petersburg 195251, RussiaLaboratory of Molecular Neurodegeneration, Peter the Great St. Petersburg Polytechnical University, St. Petersburg 195251, RussiaLaboratory of Molecular Neurodegeneration, Peter the Great St. Petersburg Polytechnical University, St. Petersburg 195251, RussiaNeurodon Corporation, 9800 Connecticut Drive, Crown Point, IN 46307, USALaboratory of Molecular Neurodegeneration, Peter the Great St. Petersburg Polytechnical University, St. Petersburg 195251, RussiaAlzheimer’s disease (AD) is a neurodegenerative disorder that affects memory formation and storage processes. Dysregulated neuronal calcium (Ca<sup>2+</sup>) has been identified as one of the key pathogenic events in AD, and it has been suggested that pharmacological agents that stabilize Ca<sup>2+</sup> neuronal signaling can act as disease-modifying agents in AD. In previous studies, we demonstrated that positive allosteric regulators (PAMs) of the sarco/endoplasmic reticulum Ca<sup>2+</sup> ATPase (SERCA) pump might act as such Ca<sup>2+</sup>-stabilizing agents and exhibit neuroprotective properties. In the present study, we evaluated effects of a set of novel SERCA PAM agents on the rate of Ca<sup>2+</sup> extraction from the cytoplasm of the HEK293T cell line, on morphometric parameters of dendritic spines of primary hippocampal neurons in normal conditions and in conditions of amyloid toxicity, and on long-term potentiation in slices derived from 5xFAD transgenic mice modeling AD. Several SERCA PAM compounds demonstrated neuroprotective properties, and the compound NDC-9009 showed the best results. The findings in this study support the hypothesis that the SERCA pump is a potential therapeutic target for AD treatment and that NDC-9009 is a promising lead molecule to be used in the development of disease-modifying agents for AD.https://www.mdpi.com/1422-0067/24/18/13973SERCApositive allosteric modulatorscalciumAlzheimer’s diseasebeta-amyloiddendritic spines |
| spellingShingle | Anastasiya Rakovskaya Alexander Erofeev Egor Vinokurov Ekaterina Pchitskaya Russell Dahl Ilya Bezprozvanny Positive Allosteric Modulators of SERCA Pump Restore Dendritic Spines and Rescue Long-Term Potentiation Defects in Alzheimer’s Disease Mouse Model International Journal of Molecular Sciences SERCA positive allosteric modulators calcium Alzheimer’s disease beta-amyloid dendritic spines |
| title | Positive Allosteric Modulators of SERCA Pump Restore Dendritic Spines and Rescue Long-Term Potentiation Defects in Alzheimer’s Disease Mouse Model |
| title_full | Positive Allosteric Modulators of SERCA Pump Restore Dendritic Spines and Rescue Long-Term Potentiation Defects in Alzheimer’s Disease Mouse Model |
| title_fullStr | Positive Allosteric Modulators of SERCA Pump Restore Dendritic Spines and Rescue Long-Term Potentiation Defects in Alzheimer’s Disease Mouse Model |
| title_full_unstemmed | Positive Allosteric Modulators of SERCA Pump Restore Dendritic Spines and Rescue Long-Term Potentiation Defects in Alzheimer’s Disease Mouse Model |
| title_short | Positive Allosteric Modulators of SERCA Pump Restore Dendritic Spines and Rescue Long-Term Potentiation Defects in Alzheimer’s Disease Mouse Model |
| title_sort | positive allosteric modulators of serca pump restore dendritic spines and rescue long term potentiation defects in alzheimer s disease mouse model |
| topic | SERCA positive allosteric modulators calcium Alzheimer’s disease beta-amyloid dendritic spines |
| url | https://www.mdpi.com/1422-0067/24/18/13973 |
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