A selective p38α/β MAPK inhibitor alleviates neuropathology and cognitive impairment, and modulates microglia function in 5XFAD mouse
Abstract Background Chronic neuroinflammation, aggressive amyloid beta (Aβ) deposition, neuronal cell loss, and cognitive impairment are pathological presentations of Alzheimer’s disease (AD). Therefore, resolution of neuroinflammation and inhibition of Aβ-driven pathology have been suggested to be...
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| Format: | Article |
| Language: | English |
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BMC
2020-04-01
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| Series: | Alzheimer’s Research & Therapy |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13195-020-00617-2 |
| _version_ | 1818513567816613888 |
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| author | Min Sung Gee Seung Hwan Son Seung Ho Jeon Jimin Do Namkwon Kim Yeon-Joo Ju Soo Jin Lee Eun Kyoung Chung Kyung-Soo Inn Nam-Jung Kim Jong Kil Lee |
| author_facet | Min Sung Gee Seung Hwan Son Seung Ho Jeon Jimin Do Namkwon Kim Yeon-Joo Ju Soo Jin Lee Eun Kyoung Chung Kyung-Soo Inn Nam-Jung Kim Jong Kil Lee |
| author_sort | Min Sung Gee |
| collection | DOAJ |
| description | Abstract Background Chronic neuroinflammation, aggressive amyloid beta (Aβ) deposition, neuronal cell loss, and cognitive impairment are pathological presentations of Alzheimer’s disease (AD). Therefore, resolution of neuroinflammation and inhibition of Aβ-driven pathology have been suggested to be important strategies for AD therapy. Previous efforts to prevent AD progression have identified p38 mitogen-activated protein kinases (MAPKs) as a promising target for AD therapy. Recent studies showed pharmacological inhibition of p38α MAPK improved memory impairment in AD mouse models. Methods In this study, we used an AD mouse model, 5XFAD, to explore the therapeutic potential of NJK14047 which is a novel, selective p38α/β MAPK inhibitor. The mice were injected with 2.5 mg/kg NJK14047 or vehicle every other day for 3 months. Morris water maze task and histological imaging analysis were performed. Protein and mRNA expression levels were measured using immunoblotting and qRT-PCR, respectively. In vitro studies were conducted to measure the cytotoxicity of microglia- and astrocyte-conditioned medium on primary neurons using the MTT assay and TUNEL assay. Results NJK14047 treatment downregulated phospho-p38 MAPK levels, decreased the amount of Aβ deposits, and reduced spatial learning memory loss in 9-month-old 5XFAD mice. While the pro-inflammatory conditions were decreased, the expression of alternatively activated microglial markers and microglial phagocytic receptors was increased. Furthermore, NJK14047 treatment reduced the number of degenerating neurons labeled with Fluoro-Jade B in the brains of 5XFAD mice. The neuroprotective effect of NJK14047 was further confirmed by in vitro studies. Conclusion Taken together, a selective p38α/β MAPK inhibitor NJK14047 successfully showed therapeutic effects for AD in 5XFAD mice. Based on our data, p38 MAPK inhibition is a potential strategy for AD therapy, suggesting NJK14047 as one of the promising candidates for AD therapeutics targeting p38 MAPKs. |
| first_indexed | 2024-12-11T00:03:14Z |
| format | Article |
| id | doaj.art-b1ea94564d774370a4ff5064f7f2dfe3 |
| institution | Directory Open Access Journal |
| issn | 1758-9193 |
| language | English |
| last_indexed | 2024-12-11T00:03:14Z |
| publishDate | 2020-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Alzheimer’s Research & Therapy |
| spelling | doaj.art-b1ea94564d774370a4ff5064f7f2dfe32022-12-22T01:28:23ZengBMCAlzheimer’s Research & Therapy1758-91932020-04-0112111810.1186/s13195-020-00617-2A selective p38α/β MAPK inhibitor alleviates neuropathology and cognitive impairment, and modulates microglia function in 5XFAD mouseMin Sung Gee0Seung Hwan Son1Seung Ho Jeon2Jimin Do3Namkwon Kim4Yeon-Joo Ju5Soo Jin Lee6Eun Kyoung Chung7Kyung-Soo Inn8Nam-Jung Kim9Jong Kil Lee10Department of Fundamental Pharmaceutical Science, Graduate School, Kyung Hee UniversityDepartment of Fundamental Pharmaceutical Science, Graduate School, Kyung Hee UniversityDepartment of Fundamental Pharmaceutical Science, Graduate School, Kyung Hee UniversityDepartment of Biomedical Science and Technology, Graduate School, Kyung Hee UniversityDepartment of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee UniversityDepartment of Fundamental Pharmaceutical Science, Graduate School, Kyung Hee UniversityDepartment of Fundamental Pharmaceutical Science, Graduate School, Kyung Hee UniversityDepartment of Fundamental Pharmaceutical Science, Graduate School, Kyung Hee UniversityDepartment of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee UniversityDepartment of Fundamental Pharmaceutical Science, Graduate School, Kyung Hee UniversityDepartment of Fundamental Pharmaceutical Science, Graduate School, Kyung Hee UniversityAbstract Background Chronic neuroinflammation, aggressive amyloid beta (Aβ) deposition, neuronal cell loss, and cognitive impairment are pathological presentations of Alzheimer’s disease (AD). Therefore, resolution of neuroinflammation and inhibition of Aβ-driven pathology have been suggested to be important strategies for AD therapy. Previous efforts to prevent AD progression have identified p38 mitogen-activated protein kinases (MAPKs) as a promising target for AD therapy. Recent studies showed pharmacological inhibition of p38α MAPK improved memory impairment in AD mouse models. Methods In this study, we used an AD mouse model, 5XFAD, to explore the therapeutic potential of NJK14047 which is a novel, selective p38α/β MAPK inhibitor. The mice were injected with 2.5 mg/kg NJK14047 or vehicle every other day for 3 months. Morris water maze task and histological imaging analysis were performed. Protein and mRNA expression levels were measured using immunoblotting and qRT-PCR, respectively. In vitro studies were conducted to measure the cytotoxicity of microglia- and astrocyte-conditioned medium on primary neurons using the MTT assay and TUNEL assay. Results NJK14047 treatment downregulated phospho-p38 MAPK levels, decreased the amount of Aβ deposits, and reduced spatial learning memory loss in 9-month-old 5XFAD mice. While the pro-inflammatory conditions were decreased, the expression of alternatively activated microglial markers and microglial phagocytic receptors was increased. Furthermore, NJK14047 treatment reduced the number of degenerating neurons labeled with Fluoro-Jade B in the brains of 5XFAD mice. The neuroprotective effect of NJK14047 was further confirmed by in vitro studies. Conclusion Taken together, a selective p38α/β MAPK inhibitor NJK14047 successfully showed therapeutic effects for AD in 5XFAD mice. Based on our data, p38 MAPK inhibition is a potential strategy for AD therapy, suggesting NJK14047 as one of the promising candidates for AD therapeutics targeting p38 MAPKs.http://link.springer.com/article/10.1186/s13195-020-00617-2Alzheimer’s diseaseAmyloid-βP38 mitogen-activated protein kinaseKinase inhibitorMicroglia |
| spellingShingle | Min Sung Gee Seung Hwan Son Seung Ho Jeon Jimin Do Namkwon Kim Yeon-Joo Ju Soo Jin Lee Eun Kyoung Chung Kyung-Soo Inn Nam-Jung Kim Jong Kil Lee A selective p38α/β MAPK inhibitor alleviates neuropathology and cognitive impairment, and modulates microglia function in 5XFAD mouse Alzheimer’s Research & Therapy Alzheimer’s disease Amyloid-β P38 mitogen-activated protein kinase Kinase inhibitor Microglia |
| title | A selective p38α/β MAPK inhibitor alleviates neuropathology and cognitive impairment, and modulates microglia function in 5XFAD mouse |
| title_full | A selective p38α/β MAPK inhibitor alleviates neuropathology and cognitive impairment, and modulates microglia function in 5XFAD mouse |
| title_fullStr | A selective p38α/β MAPK inhibitor alleviates neuropathology and cognitive impairment, and modulates microglia function in 5XFAD mouse |
| title_full_unstemmed | A selective p38α/β MAPK inhibitor alleviates neuropathology and cognitive impairment, and modulates microglia function in 5XFAD mouse |
| title_short | A selective p38α/β MAPK inhibitor alleviates neuropathology and cognitive impairment, and modulates microglia function in 5XFAD mouse |
| title_sort | selective p38α β mapk inhibitor alleviates neuropathology and cognitive impairment and modulates microglia function in 5xfad mouse |
| topic | Alzheimer’s disease Amyloid-β P38 mitogen-activated protein kinase Kinase inhibitor Microglia |
| url | http://link.springer.com/article/10.1186/s13195-020-00617-2 |
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