The STIM1/2-Regulated Calcium Homeostasis Is Impaired in Hippocampal Neurons of the 5xFAD Mouse Model of Alzheimer’s Disease
Alzheimer’s disease (AD) is the most common cause of age-related dementia. Neuronal calcium homeostasis impairment may contribute to AD. Here we demonstrated that voltage-gated calcium (VGC) entry and store-operated calcium (SOC) entry regulated by calcium sensors of intracellular calcium stores STI...
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MDPI AG
2022-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/23/14810 |
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| author | Ksenia Skobeleva Alexey Shalygin Elena Mikhaylova Irina Guzhova Maria Ryazantseva Elena Kaznacheyeva |
| author_facet | Ksenia Skobeleva Alexey Shalygin Elena Mikhaylova Irina Guzhova Maria Ryazantseva Elena Kaznacheyeva |
| author_sort | Ksenia Skobeleva |
| collection | DOAJ |
| description | Alzheimer’s disease (AD) is the most common cause of age-related dementia. Neuronal calcium homeostasis impairment may contribute to AD. Here we demonstrated that voltage-gated calcium (VGC) entry and store-operated calcium (SOC) entry regulated by calcium sensors of intracellular calcium stores STIM proteins are affected in hippocampal neurons of the 5xFAD transgenic mouse model. We observed excessive SOC entry in 5xFAD mouse neurons, mediated by STIM1 and STIM2 proteins with increased STIM1 contribution. There were no significant changes in cytoplasmic calcium level, endoplasmic reticulum (ER) bulk calcium levels, or expression levels of STIM1 or STIM2 proteins. The potent inhibitor BTP-2 and the FDA-approved drug leflunomide reduced SOC entry in 5xFAD neurons. In turn, excessive voltage-gated calcium entry was sensitive to the inhibitor of L-type calcium channels nifedipine but not to the T-type channels inhibitor ML218. Interestingly, the depolarization-induced calcium entry mediated by VGC channels in 5xFAD neurons was dependent on STIM2 but not STIM1 protein in cells with replete Ca<sup>2+</sup> stores. The result gives new evidence on the VGC channel modulation by STIM2. Overall, the data demonstrate the changes in calcium signaling of hippocampal neurons of the AD mouse model, which precede amyloid plaque accumulation or other signs of pathology manifestation. |
| first_indexed | 2024-03-09T17:46:11Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T17:46:11Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-1da836fe301c405baf7e4ba34a464d392023-11-24T11:08:16ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-11-0123231481010.3390/ijms232314810The STIM1/2-Regulated Calcium Homeostasis Is Impaired in Hippocampal Neurons of the 5xFAD Mouse Model of Alzheimer’s DiseaseKsenia Skobeleva0Alexey Shalygin1Elena Mikhaylova2Irina Guzhova3Maria Ryazantseva4Elena Kaznacheyeva5Institute of Cytology of the Russian Academy of Sciences (RAS), 194064 St. Petersburg, RussiaInstitute of Cytology of the Russian Academy of Sciences (RAS), 194064 St. Petersburg, RussiaInstitute of Cytology of the Russian Academy of Sciences (RAS), 194064 St. Petersburg, RussiaInstitute of Cytology of the Russian Academy of Sciences (RAS), 194064 St. Petersburg, RussiaNeuroscience Center, University of Helsinki, HiLIFE, P.O. Box 63, 00014 Helsinki, FinlandInstitute of Cytology of the Russian Academy of Sciences (RAS), 194064 St. Petersburg, RussiaAlzheimer’s disease (AD) is the most common cause of age-related dementia. Neuronal calcium homeostasis impairment may contribute to AD. Here we demonstrated that voltage-gated calcium (VGC) entry and store-operated calcium (SOC) entry regulated by calcium sensors of intracellular calcium stores STIM proteins are affected in hippocampal neurons of the 5xFAD transgenic mouse model. We observed excessive SOC entry in 5xFAD mouse neurons, mediated by STIM1 and STIM2 proteins with increased STIM1 contribution. There were no significant changes in cytoplasmic calcium level, endoplasmic reticulum (ER) bulk calcium levels, or expression levels of STIM1 or STIM2 proteins. The potent inhibitor BTP-2 and the FDA-approved drug leflunomide reduced SOC entry in 5xFAD neurons. In turn, excessive voltage-gated calcium entry was sensitive to the inhibitor of L-type calcium channels nifedipine but not to the T-type channels inhibitor ML218. Interestingly, the depolarization-induced calcium entry mediated by VGC channels in 5xFAD neurons was dependent on STIM2 but not STIM1 protein in cells with replete Ca<sup>2+</sup> stores. The result gives new evidence on the VGC channel modulation by STIM2. Overall, the data demonstrate the changes in calcium signaling of hippocampal neurons of the AD mouse model, which precede amyloid plaque accumulation or other signs of pathology manifestation.https://www.mdpi.com/1422-0067/23/23/14810Alzheimer’s disease5xFADhippocampal culturesstore-operated calcium entryvoltage-gated calcium entrySTIM1 |
| spellingShingle | Ksenia Skobeleva Alexey Shalygin Elena Mikhaylova Irina Guzhova Maria Ryazantseva Elena Kaznacheyeva The STIM1/2-Regulated Calcium Homeostasis Is Impaired in Hippocampal Neurons of the 5xFAD Mouse Model of Alzheimer’s Disease International Journal of Molecular Sciences Alzheimer’s disease 5xFAD hippocampal cultures store-operated calcium entry voltage-gated calcium entry STIM1 |
| title | The STIM1/2-Regulated Calcium Homeostasis Is Impaired in Hippocampal Neurons of the 5xFAD Mouse Model of Alzheimer’s Disease |
| title_full | The STIM1/2-Regulated Calcium Homeostasis Is Impaired in Hippocampal Neurons of the 5xFAD Mouse Model of Alzheimer’s Disease |
| title_fullStr | The STIM1/2-Regulated Calcium Homeostasis Is Impaired in Hippocampal Neurons of the 5xFAD Mouse Model of Alzheimer’s Disease |
| title_full_unstemmed | The STIM1/2-Regulated Calcium Homeostasis Is Impaired in Hippocampal Neurons of the 5xFAD Mouse Model of Alzheimer’s Disease |
| title_short | The STIM1/2-Regulated Calcium Homeostasis Is Impaired in Hippocampal Neurons of the 5xFAD Mouse Model of Alzheimer’s Disease |
| title_sort | stim1 2 regulated calcium homeostasis is impaired in hippocampal neurons of the 5xfad mouse model of alzheimer s disease |
| topic | Alzheimer’s disease 5xFAD hippocampal cultures store-operated calcium entry voltage-gated calcium entry STIM1 |
| url | https://www.mdpi.com/1422-0067/23/23/14810 |
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