Positive Allosteric Modulator of SERCA Pump NDC-1173 Exerts Beneficial Effects in Mouse Model of Alzheimer’s Disease
Alzheimer’s disease (AD) is an irreversible neurodegenerative disease that affects millions of people worldwide. AD does not have a cure and most drug development efforts in the AD field have been focused on targeting the amyloid pathway based on the “amyloid cascade hypothesis”. However, in additio...
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| Format: | Article |
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MDPI AG
2023-07-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/13/11057 |
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| author | Russell Dahl Amanda C. Moore Caitlynn Knight Colleen Mauger Hua Zhang Gary E. Schiltz Wendy A. Koss Ilya Bezprozvanny |
| author_facet | Russell Dahl Amanda C. Moore Caitlynn Knight Colleen Mauger Hua Zhang Gary E. Schiltz Wendy A. Koss Ilya Bezprozvanny |
| author_sort | Russell Dahl |
| collection | DOAJ |
| description | Alzheimer’s disease (AD) is an irreversible neurodegenerative disease that affects millions of people worldwide. AD does not have a cure and most drug development efforts in the AD field have been focused on targeting the amyloid pathway based on the “amyloid cascade hypothesis”. However, in addition to the amyloid pathway, substantial evidence also points to dysregulated neuronal calcium (Ca<sup>2+</sup>) signaling as one of the key pathogenic events in AD, and it has been proposed that pharmacological agents that stabilize neuronal Ca<sup>2+</sup> signaling may 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. In the present study, we report the development of a novel SERCA PAM agent, compound NDC-1173. To test the effectiveness of this compound, we performed behavioral studies with the APP/PS1 transgenic AD mouse model. We also evaluated effects of this compound on expression of endoplasmic reticulum (ER) stress genes in the hippocampus of APP/PS1 mice. The results of this study support the hypothesis that the SERCA pump is a potential novel therapeutic drug target and that NDC-1173 is a promising lead molecule for developing disease-modifying agents in AD. |
| first_indexed | 2024-03-11T01:38:39Z |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T01:38:39Z |
| publishDate | 2023-07-01 |
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| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-fab31ecf099c4babbb8987c5c8b65d632023-11-18T16:47:29ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-07-0124131105710.3390/ijms241311057Positive Allosteric Modulator of SERCA Pump NDC-1173 Exerts Beneficial Effects in Mouse Model of Alzheimer’s DiseaseRussell Dahl0Amanda C. Moore1Caitlynn Knight2Colleen Mauger3Hua Zhang4Gary E. Schiltz5Wendy A. Koss6Ilya Bezprozvanny7Neurodon, 9800 Connecticut Drive, Crown Point, IN 46307, USAPurdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN 47907, USADepartment of Physiology, UT Southwestern Medical Center at Dallas, Dallas, TX 75390, USANeurodon, 9800 Connecticut Drive, Crown Point, IN 46307, USADepartment of Physiology, UT Southwestern Medical Center at Dallas, Dallas, TX 75390, USADepartment of Chemistry, Northwestern University, Evanston, IL 60208, USAPurdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN 47907, USADepartment of Physiology, UT Southwestern Medical Center at Dallas, Dallas, TX 75390, USAAlzheimer’s disease (AD) is an irreversible neurodegenerative disease that affects millions of people worldwide. AD does not have a cure and most drug development efforts in the AD field have been focused on targeting the amyloid pathway based on the “amyloid cascade hypothesis”. However, in addition to the amyloid pathway, substantial evidence also points to dysregulated neuronal calcium (Ca<sup>2+</sup>) signaling as one of the key pathogenic events in AD, and it has been proposed that pharmacological agents that stabilize neuronal Ca<sup>2+</sup> signaling may 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. In the present study, we report the development of a novel SERCA PAM agent, compound NDC-1173. To test the effectiveness of this compound, we performed behavioral studies with the APP/PS1 transgenic AD mouse model. We also evaluated effects of this compound on expression of endoplasmic reticulum (ER) stress genes in the hippocampus of APP/PS1 mice. The results of this study support the hypothesis that the SERCA pump is a potential novel therapeutic drug target and that NDC-1173 is a promising lead molecule for developing disease-modifying agents in AD.https://www.mdpi.com/1422-0067/24/13/11057SERCAcalciumAlzheimer’s diseasedrug developmentbehaviorER stress |
| spellingShingle | Russell Dahl Amanda C. Moore Caitlynn Knight Colleen Mauger Hua Zhang Gary E. Schiltz Wendy A. Koss Ilya Bezprozvanny Positive Allosteric Modulator of SERCA Pump NDC-1173 Exerts Beneficial Effects in Mouse Model of Alzheimer’s Disease International Journal of Molecular Sciences SERCA calcium Alzheimer’s disease drug development behavior ER stress |
| title | Positive Allosteric Modulator of SERCA Pump NDC-1173 Exerts Beneficial Effects in Mouse Model of Alzheimer’s Disease |
| title_full | Positive Allosteric Modulator of SERCA Pump NDC-1173 Exerts Beneficial Effects in Mouse Model of Alzheimer’s Disease |
| title_fullStr | Positive Allosteric Modulator of SERCA Pump NDC-1173 Exerts Beneficial Effects in Mouse Model of Alzheimer’s Disease |
| title_full_unstemmed | Positive Allosteric Modulator of SERCA Pump NDC-1173 Exerts Beneficial Effects in Mouse Model of Alzheimer’s Disease |
| title_short | Positive Allosteric Modulator of SERCA Pump NDC-1173 Exerts Beneficial Effects in Mouse Model of Alzheimer’s Disease |
| title_sort | positive allosteric modulator of serca pump ndc 1173 exerts beneficial effects in mouse model of alzheimer s disease |
| topic | SERCA calcium Alzheimer’s disease drug development behavior ER stress |
| url | https://www.mdpi.com/1422-0067/24/13/11057 |
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