Gentiacaulein inhibits glucose transport to induce PRKAA1-mediated autophagy to clear amyloid beta and associated inflammation in primary astrocytes
Being present in substantial numbers, astrocytes play an indispensable role in maintaining homeostasis in the brain. However, their positive or negative involvement in pathological conditions in the brain has not been explored much. In recent years, an emerging thought of targeting astrocytes for th...
Saved in:
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2024-12-01
|
| Series: | Autophagy Reports |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/27694127.2023.2296209 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850137977043288064 |
|---|---|
| author | Ankita Sharma Sukhleen Kaur Abubakar Wani Dilpreet Kour Mehboob Ali Syed Mudassir Ali Lakhvinder Singh Abhishek Gour Utpal Nandi Manish Datt Parduman Raj Sharma Conrad C Weihl Gurdarshan Singh Ajay Kumar |
| author_facet | Ankita Sharma Sukhleen Kaur Abubakar Wani Dilpreet Kour Mehboob Ali Syed Mudassir Ali Lakhvinder Singh Abhishek Gour Utpal Nandi Manish Datt Parduman Raj Sharma Conrad C Weihl Gurdarshan Singh Ajay Kumar |
| author_sort | Ankita Sharma |
| collection | DOAJ |
| description | Being present in substantial numbers, astrocytes play an indispensable role in maintaining homeostasis in the brain. However, their positive or negative involvement in pathological conditions in the brain has not been explored much. In recent years, an emerging thought of targeting astrocytes for the resolution of neurodegenerative diseases has gained momentum. In this study, we have attempted to explore the likelihood of targeting astrocytes by using a natural compound, gentiacaulein (GENT), for clearance of amyloid-β (Aβ) through autophagy and amelioration of neuroinflammation associated with Aβ. We found that GENT treatment of astrocytes hampered the transport of glucose across the cell membrane, which resulted in a reduction in ATP production. With increased treatment time, AMP: ATP ratio was increased significantly, which caused the induction of PRKAA1-mediated autophagy. We further show that increased autophagy considerably enhanced the clearance of amyloid-β by astrocytes. GENT reduced the Aβ mediated inflammation by inhibiting the nuclear translocation of NF-κB and decreased the release of inflammatory cytokines TNF-α and IL-6. The role of PRKAA1 in GENT-induced autophagy and anti-inflammatory activity was confirmed when its knockdown reversed these effects. Our data suggest that targeting astrocytes can be a good strategy to prevent/treat Alzheimer’s disease. |
| format | Article |
| id | doaj-art-25c78f4100fa46be8e209b6d79865ea0 |
| institution | OA Journals |
| issn | 2769-4127 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Autophagy Reports |
| spelling | doaj-art-25c78f4100fa46be8e209b6d79865ea02025-08-20T02:30:42ZengTaylor & Francis GroupAutophagy Reports2769-41272024-12-013110.1080/27694127.2023.2296209Gentiacaulein inhibits glucose transport to induce PRKAA1-mediated autophagy to clear amyloid beta and associated inflammation in primary astrocytesAnkita Sharma0Sukhleen Kaur1Abubakar Wani2Dilpreet Kour3Mehboob Ali4Syed Mudassir Ali5Lakhvinder Singh6Abhishek Gour7Utpal Nandi8Manish Datt9Parduman Raj Sharma10Conrad C Weihl11Gurdarshan Singh12Ajay Kumar13PK-PD-Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu-180001, IndiaPK-PD-Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu-180001, IndiaDepartment of Immunology, St Jude children’s Hospital, Memphis, TN 38105, USAPK-PD-Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu-180001, IndiaPK-PD-Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu-180001, IndiaPK-PD-Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu-180001, IndiaPK-PD-Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu-180001, IndiaPK-PD-Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu-180001, IndiaPK-PD-Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu-180001, IndiaBiological and Life Sciences Division, Institute of Life Sciences, Ahmedabad University, Ahmedabad, Gujarat - 380009, IndiaPharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu-180001, IndiaDepartment of Neurology, Hope Center for Neurological Diseases, Washington University School of Medicine, St. Louis, MO, USAPK-PD-Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu-180001, IndiaPK-PD-Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu-180001, IndiaBeing present in substantial numbers, astrocytes play an indispensable role in maintaining homeostasis in the brain. However, their positive or negative involvement in pathological conditions in the brain has not been explored much. In recent years, an emerging thought of targeting astrocytes for the resolution of neurodegenerative diseases has gained momentum. In this study, we have attempted to explore the likelihood of targeting astrocytes by using a natural compound, gentiacaulein (GENT), for clearance of amyloid-β (Aβ) through autophagy and amelioration of neuroinflammation associated with Aβ. We found that GENT treatment of astrocytes hampered the transport of glucose across the cell membrane, which resulted in a reduction in ATP production. With increased treatment time, AMP: ATP ratio was increased significantly, which caused the induction of PRKAA1-mediated autophagy. We further show that increased autophagy considerably enhanced the clearance of amyloid-β by astrocytes. GENT reduced the Aβ mediated inflammation by inhibiting the nuclear translocation of NF-κB and decreased the release of inflammatory cytokines TNF-α and IL-6. The role of PRKAA1 in GENT-induced autophagy and anti-inflammatory activity was confirmed when its knockdown reversed these effects. Our data suggest that targeting astrocytes can be a good strategy to prevent/treat Alzheimer’s disease.https://www.tandfonline.com/doi/10.1080/27694127.2023.2296209Alzheimer diseaseAmyloid-βAstrocytesAutophagyGentiacauleinNeuroinflammation |
| spellingShingle | Ankita Sharma Sukhleen Kaur Abubakar Wani Dilpreet Kour Mehboob Ali Syed Mudassir Ali Lakhvinder Singh Abhishek Gour Utpal Nandi Manish Datt Parduman Raj Sharma Conrad C Weihl Gurdarshan Singh Ajay Kumar Gentiacaulein inhibits glucose transport to induce PRKAA1-mediated autophagy to clear amyloid beta and associated inflammation in primary astrocytes Autophagy Reports Alzheimer disease Amyloid-β Astrocytes Autophagy Gentiacaulein Neuroinflammation |
| title | Gentiacaulein inhibits glucose transport to induce PRKAA1-mediated autophagy to clear amyloid beta and associated inflammation in primary astrocytes |
| title_full | Gentiacaulein inhibits glucose transport to induce PRKAA1-mediated autophagy to clear amyloid beta and associated inflammation in primary astrocytes |
| title_fullStr | Gentiacaulein inhibits glucose transport to induce PRKAA1-mediated autophagy to clear amyloid beta and associated inflammation in primary astrocytes |
| title_full_unstemmed | Gentiacaulein inhibits glucose transport to induce PRKAA1-mediated autophagy to clear amyloid beta and associated inflammation in primary astrocytes |
| title_short | Gentiacaulein inhibits glucose transport to induce PRKAA1-mediated autophagy to clear amyloid beta and associated inflammation in primary astrocytes |
| title_sort | gentiacaulein inhibits glucose transport to induce prkaa1 mediated autophagy to clear amyloid beta and associated inflammation in primary astrocytes |
| topic | Alzheimer disease Amyloid-β Astrocytes Autophagy Gentiacaulein Neuroinflammation |
| url | https://www.tandfonline.com/doi/10.1080/27694127.2023.2296209 |
| work_keys_str_mv | AT ankitasharma gentiacauleininhibitsglucosetransporttoinduceprkaa1mediatedautophagytoclearamyloidbetaandassociatedinflammationinprimaryastrocytes AT sukhleenkaur gentiacauleininhibitsglucosetransporttoinduceprkaa1mediatedautophagytoclearamyloidbetaandassociatedinflammationinprimaryastrocytes AT abubakarwani gentiacauleininhibitsglucosetransporttoinduceprkaa1mediatedautophagytoclearamyloidbetaandassociatedinflammationinprimaryastrocytes AT dilpreetkour gentiacauleininhibitsglucosetransporttoinduceprkaa1mediatedautophagytoclearamyloidbetaandassociatedinflammationinprimaryastrocytes AT mehboobali gentiacauleininhibitsglucosetransporttoinduceprkaa1mediatedautophagytoclearamyloidbetaandassociatedinflammationinprimaryastrocytes AT syedmudassirali gentiacauleininhibitsglucosetransporttoinduceprkaa1mediatedautophagytoclearamyloidbetaandassociatedinflammationinprimaryastrocytes AT lakhvindersingh gentiacauleininhibitsglucosetransporttoinduceprkaa1mediatedautophagytoclearamyloidbetaandassociatedinflammationinprimaryastrocytes AT abhishekgour gentiacauleininhibitsglucosetransporttoinduceprkaa1mediatedautophagytoclearamyloidbetaandassociatedinflammationinprimaryastrocytes AT utpalnandi gentiacauleininhibitsglucosetransporttoinduceprkaa1mediatedautophagytoclearamyloidbetaandassociatedinflammationinprimaryastrocytes AT manishdatt gentiacauleininhibitsglucosetransporttoinduceprkaa1mediatedautophagytoclearamyloidbetaandassociatedinflammationinprimaryastrocytes AT pardumanrajsharma gentiacauleininhibitsglucosetransporttoinduceprkaa1mediatedautophagytoclearamyloidbetaandassociatedinflammationinprimaryastrocytes AT conradcweihl gentiacauleininhibitsglucosetransporttoinduceprkaa1mediatedautophagytoclearamyloidbetaandassociatedinflammationinprimaryastrocytes AT gurdarshansingh gentiacauleininhibitsglucosetransporttoinduceprkaa1mediatedautophagytoclearamyloidbetaandassociatedinflammationinprimaryastrocytes AT ajaykumar gentiacauleininhibitsglucosetransporttoinduceprkaa1mediatedautophagytoclearamyloidbetaandassociatedinflammationinprimaryastrocytes |