Methionine Aminopeptidase 2 (MetAP2) Inhibitor BL6 Attenuates Inflammation in Cultured Microglia and in a Mouse Model of Alzheimer’s Disease
Methionine aminopeptidase 2 (MetAP2) plays an important role in the regulation of protein synthesis and post-translational processing. Preclinical/clinical applications of MetAP2 inhibitors for the treatment of various diseases have been explored because of their antiangiogenic, anticancer, antiobes...
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2025-01-01
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| author | Xiuli Zhang Shivakumar Subbanna Colin R. O. Williams Stefanie Canals-Baker Audrey Hashim Donald A. Wilson Louis M. Weiss Srushti Shukla Parthiban Chokkalingam Sasmita Das Bhaskar C. Das Mariko Saito |
| author_facet | Xiuli Zhang Shivakumar Subbanna Colin R. O. Williams Stefanie Canals-Baker Audrey Hashim Donald A. Wilson Louis M. Weiss Srushti Shukla Parthiban Chokkalingam Sasmita Das Bhaskar C. Das Mariko Saito |
| author_sort | Xiuli Zhang |
| collection | DOAJ |
| description | Methionine aminopeptidase 2 (MetAP2) plays an important role in the regulation of protein synthesis and post-translational processing. Preclinical/clinical applications of MetAP2 inhibitors for the treatment of various diseases have been explored because of their antiangiogenic, anticancer, antiobesity, antidiabetic, and immunosuppressive properties. However, the effects of MetAP2 inhibitors on CNS diseases are rarely examined despite the abundant presence of MetAP2 in the brain. Previously, we synthesized a novel boron-containing MetAP2 inhibitor, BL6, and found that it suppressed angiogenesis and adipogenesis yet improved glucose uptake. Here, we studied the anti-inflammatory effects of BL6 in SIM-A9 microglia and in a mouse model of Alzheimer’s disease generated by the intracerebroventricular (icv) injection of streptozotocin (STZ). We found that BL6 reduced proinflammatory molecules, such as nitric oxide, iNOS, IL-1β, and IL-6, together with phospho-Akt and phospho-NF-κB p65, which were elevated in lipopolysaccharide (LPS)-activated microglial SIM-A9 cells. However, the LPS-induced reduction in Arg-1 and CD206 was attenuated by BL6, suggesting that BL6 promotes microglial M1 to M2 polarization. BL6 also decreased glial activation along with a reduction in phospho-tau and an elevation in synaptophysin in the icv-STZ mouse model. Thus, our experiments demonstrate an anti-neuroinflammatory action of BL6, suggesting possible clinical applications of MetAP2 inhibitors for brain disorders in which neuroinflammation is involved. |
| format | Article |
| id | doaj-art-37e5d7fbdad6452aa5dc85b962d9937b |
| institution | DOAJ |
| issn | 1420-3049 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj-art-37e5d7fbdad6452aa5dc85b962d9937b2025-08-20T02:48:07ZengMDPI AGMolecules1420-30492025-01-0130362010.3390/molecules30030620Methionine Aminopeptidase 2 (MetAP2) Inhibitor BL6 Attenuates Inflammation in Cultured Microglia and in a Mouse Model of Alzheimer’s DiseaseXiuli Zhang0Shivakumar Subbanna1Colin R. O. Williams2Stefanie Canals-Baker3Audrey Hashim4Donald A. Wilson5Louis M. Weiss6Srushti Shukla7Parthiban Chokkalingam8Sasmita Das9Bhaskar C. Das10Mariko Saito11Division of Neurochemistry, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USADivision of Neurochemistry, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USAEmotional Brain Institute, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USADivision of Neurochemistry, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USADivision of Neurochemistry, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USAEmotional Brain Institute, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USADepartment of Pathology/Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USASchool of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14201, USASchool of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14201, USASchool of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14201, USASchool of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14201, USADivision of Neurochemistry, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USAMethionine aminopeptidase 2 (MetAP2) plays an important role in the regulation of protein synthesis and post-translational processing. Preclinical/clinical applications of MetAP2 inhibitors for the treatment of various diseases have been explored because of their antiangiogenic, anticancer, antiobesity, antidiabetic, and immunosuppressive properties. However, the effects of MetAP2 inhibitors on CNS diseases are rarely examined despite the abundant presence of MetAP2 in the brain. Previously, we synthesized a novel boron-containing MetAP2 inhibitor, BL6, and found that it suppressed angiogenesis and adipogenesis yet improved glucose uptake. Here, we studied the anti-inflammatory effects of BL6 in SIM-A9 microglia and in a mouse model of Alzheimer’s disease generated by the intracerebroventricular (icv) injection of streptozotocin (STZ). We found that BL6 reduced proinflammatory molecules, such as nitric oxide, iNOS, IL-1β, and IL-6, together with phospho-Akt and phospho-NF-κB p65, which were elevated in lipopolysaccharide (LPS)-activated microglial SIM-A9 cells. However, the LPS-induced reduction in Arg-1 and CD206 was attenuated by BL6, suggesting that BL6 promotes microglial M1 to M2 polarization. BL6 also decreased glial activation along with a reduction in phospho-tau and an elevation in synaptophysin in the icv-STZ mouse model. Thus, our experiments demonstrate an anti-neuroinflammatory action of BL6, suggesting possible clinical applications of MetAP2 inhibitors for brain disorders in which neuroinflammation is involved.https://www.mdpi.com/1420-3049/30/3/620MetAP2 inhibitorsmicroglianeuroinflammationSIM-A9icv-STZAlzheimer’s disease |
| spellingShingle | Xiuli Zhang Shivakumar Subbanna Colin R. O. Williams Stefanie Canals-Baker Audrey Hashim Donald A. Wilson Louis M. Weiss Srushti Shukla Parthiban Chokkalingam Sasmita Das Bhaskar C. Das Mariko Saito Methionine Aminopeptidase 2 (MetAP2) Inhibitor BL6 Attenuates Inflammation in Cultured Microglia and in a Mouse Model of Alzheimer’s Disease Molecules MetAP2 inhibitors microglia neuroinflammation SIM-A9 icv-STZ Alzheimer’s disease |
| title | Methionine Aminopeptidase 2 (MetAP2) Inhibitor BL6 Attenuates Inflammation in Cultured Microglia and in a Mouse Model of Alzheimer’s Disease |
| title_full | Methionine Aminopeptidase 2 (MetAP2) Inhibitor BL6 Attenuates Inflammation in Cultured Microglia and in a Mouse Model of Alzheimer’s Disease |
| title_fullStr | Methionine Aminopeptidase 2 (MetAP2) Inhibitor BL6 Attenuates Inflammation in Cultured Microglia and in a Mouse Model of Alzheimer’s Disease |
| title_full_unstemmed | Methionine Aminopeptidase 2 (MetAP2) Inhibitor BL6 Attenuates Inflammation in Cultured Microglia and in a Mouse Model of Alzheimer’s Disease |
| title_short | Methionine Aminopeptidase 2 (MetAP2) Inhibitor BL6 Attenuates Inflammation in Cultured Microglia and in a Mouse Model of Alzheimer’s Disease |
| title_sort | methionine aminopeptidase 2 metap2 inhibitor bl6 attenuates inflammation in cultured microglia and in a mouse model of alzheimer s disease |
| topic | MetAP2 inhibitors microglia neuroinflammation SIM-A9 icv-STZ Alzheimer’s disease |
| url | https://www.mdpi.com/1420-3049/30/3/620 |
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