Dabigatran reduces thrombin-induced neuroinflammation and AD markers in vitro: Therapeutic relevance for Alzheimer's disease
Background: Vascular risk factors such as atherosclerosis, diabetes, and elevated homocysteine levels are strongly correlated with onset of Alzheimer's disease (AD). Emerging evidence indicates that blood coagulation protein thrombin is associated with vascular and non-vascular risk factors of...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-01-01
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| Series: | Cerebral Circulation - Cognition and Behavior |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666245021000118 |
| _version_ | 1797967056919855104 |
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| author | Syed Waseem Bihaqi Haripriya Vittal Rao Abhik Sen Paula Grammas |
| author_facet | Syed Waseem Bihaqi Haripriya Vittal Rao Abhik Sen Paula Grammas |
| author_sort | Syed Waseem Bihaqi |
| collection | DOAJ |
| description | Background: Vascular risk factors such as atherosclerosis, diabetes, and elevated homocysteine levels are strongly correlated with onset of Alzheimer's disease (AD). Emerging evidence indicates that blood coagulation protein thrombin is associated with vascular and non-vascular risk factors of AD. Here, we examined the effect of thrombin and its direct inhibitor dabigatran on key mediators of neuro-inflammation and AD pathology in the retinoic acid (RA)-differentiated human neuroblastoma cell line SH-SY5Y. Methods: SH-SY5Y cells exposed to thrombin concentrations (10–100 nM) +/- 250 nM dabigatran for 24 h were analyzed for protein and gene expression. Electrophoretic mobility shift assay (EMSA) was used to determine DNA binding of NFkB. Western blotting, qRT-PCR and ELISA were used to measure the protein, mRNA, and activity levels of known AD hallmarks and signaling molecules. Results: Dabigatran treatment attenuated thrombin-induced increase in DNA binding of NFκB by 175% at 50 nM and by 77% at 100 nM thrombin concentration. Thrombin also augmented accumulation of Aβ protein expression and phosphorylation of p38 MAPK, a downstream molecule in the signaling cascade, expression of pro-apoptotic mediator caspase 3, APP, tTau and pTau. Additionally, thrombin increased BACE1 activity, GSK3β expression, and APP, BACE1, Tau and GSK3β mRNA levels. Co-incubation with dabigatran attenuated thrombin-induced increases in the protein, mRNA, and activities of the aforesaid molecules to various extents (between −31% and −283%). Conclusion: Our data demonstrates that thrombin promotes AD-related pathological changes in neuronal cultures and suggests that use of direct oral anticoagulants may provide a therapeutic benefit against thrombin-driven neuroinflammation and downstream pathology in AD. |
| first_indexed | 2024-04-11T02:24:06Z |
| format | Article |
| id | doaj.art-c2c83101daef4c86bf2e9b6a1b98fcd5 |
| institution | Directory Open Access Journal |
| issn | 2666-2450 |
| language | English |
| last_indexed | 2024-04-11T02:24:06Z |
| publishDate | 2021-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cerebral Circulation - Cognition and Behavior |
| spelling | doaj.art-c2c83101daef4c86bf2e9b6a1b98fcd52023-01-02T23:00:03ZengElsevierCerebral Circulation - Cognition and Behavior2666-24502021-01-012100014Dabigatran reduces thrombin-induced neuroinflammation and AD markers in vitro: Therapeutic relevance for Alzheimer's diseaseSyed Waseem Bihaqi0Haripriya Vittal Rao1Abhik Sen2Paula Grammas3George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI 02881, United States; Department of Pathology, Anatomy and Cell biology, Thomas Jefferson University, Philadelphia, PA 19107, United States; Corresponding author at: Department of Pathology, Anatomy and Cell biology, 1020 Locust Street, Jefferson Alumni Hall, Thomas Jefferson University, Philadelphia, PA 19107, United States.George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI 02881, United States; Wake Forest Alzheimer's Disease Research Center, Winston Salem, NC 27101, United StatesGeorge & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI 02881, United States; ICMR-Rajendra Memorial Research Institute of Medical Sciences, Patna, IndiaGeorge & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI 02881, United States; Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, United StatesBackground: Vascular risk factors such as atherosclerosis, diabetes, and elevated homocysteine levels are strongly correlated with onset of Alzheimer's disease (AD). Emerging evidence indicates that blood coagulation protein thrombin is associated with vascular and non-vascular risk factors of AD. Here, we examined the effect of thrombin and its direct inhibitor dabigatran on key mediators of neuro-inflammation and AD pathology in the retinoic acid (RA)-differentiated human neuroblastoma cell line SH-SY5Y. Methods: SH-SY5Y cells exposed to thrombin concentrations (10–100 nM) +/- 250 nM dabigatran for 24 h were analyzed for protein and gene expression. Electrophoretic mobility shift assay (EMSA) was used to determine DNA binding of NFkB. Western blotting, qRT-PCR and ELISA were used to measure the protein, mRNA, and activity levels of known AD hallmarks and signaling molecules. Results: Dabigatran treatment attenuated thrombin-induced increase in DNA binding of NFκB by 175% at 50 nM and by 77% at 100 nM thrombin concentration. Thrombin also augmented accumulation of Aβ protein expression and phosphorylation of p38 MAPK, a downstream molecule in the signaling cascade, expression of pro-apoptotic mediator caspase 3, APP, tTau and pTau. Additionally, thrombin increased BACE1 activity, GSK3β expression, and APP, BACE1, Tau and GSK3β mRNA levels. Co-incubation with dabigatran attenuated thrombin-induced increases in the protein, mRNA, and activities of the aforesaid molecules to various extents (between −31% and −283%). Conclusion: Our data demonstrates that thrombin promotes AD-related pathological changes in neuronal cultures and suggests that use of direct oral anticoagulants may provide a therapeutic benefit against thrombin-driven neuroinflammation and downstream pathology in AD.http://www.sciencedirect.com/science/article/pii/S2666245021000118Alzheimer's DiseaseAβNFκBDabigatranSH-SY5YThrombin |
| spellingShingle | Syed Waseem Bihaqi Haripriya Vittal Rao Abhik Sen Paula Grammas Dabigatran reduces thrombin-induced neuroinflammation and AD markers in vitro: Therapeutic relevance for Alzheimer's disease Cerebral Circulation - Cognition and Behavior Alzheimer's Disease Aβ NFκB Dabigatran SH-SY5Y Thrombin |
| title | Dabigatran reduces thrombin-induced neuroinflammation and AD markers in vitro: Therapeutic relevance for Alzheimer's disease |
| title_full | Dabigatran reduces thrombin-induced neuroinflammation and AD markers in vitro: Therapeutic relevance for Alzheimer's disease |
| title_fullStr | Dabigatran reduces thrombin-induced neuroinflammation and AD markers in vitro: Therapeutic relevance for Alzheimer's disease |
| title_full_unstemmed | Dabigatran reduces thrombin-induced neuroinflammation and AD markers in vitro: Therapeutic relevance for Alzheimer's disease |
| title_short | Dabigatran reduces thrombin-induced neuroinflammation and AD markers in vitro: Therapeutic relevance for Alzheimer's disease |
| title_sort | dabigatran reduces thrombin induced neuroinflammation and ad markers in vitro therapeutic relevance for alzheimer s disease |
| topic | Alzheimer's Disease Aβ NFκB Dabigatran SH-SY5Y Thrombin |
| url | http://www.sciencedirect.com/science/article/pii/S2666245021000118 |
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