Isobavachalcone ameliorates Alzheimer disease pathology by autophagy-mediated clearance of amyloid beta and inhibition of NLRP3 inflammasome in primary astrocytes and 5x-FAD mice
Background and AimAlzheimer’s disease (AD) progresses with Aβ plaque deposition and neuroinflammation. Given the complexity of AD pathology, single-target therapies have frequently failed in clinical trials. We hypothesized that a multitarget approach could yield better therapeutic outcomes. To this...
Saved in:
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2025-03-01
|
| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2025.1525364/full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849343720677179392 |
|---|---|
| author | Dilpreet Kour Dilpreet Kour Parul Khajuria Parul Khajuria Kuhu Sharma Kuhu Sharma Alpa Sharma Alpa Sharma Ankita Sharma Ankita Sharma Syed Mudassir Ali Priya Wazir P. Ramajayan P. Ramajayan Sanghapal D. Sawant Sanghapal D. Sawant Sanghapal D. Sawant Utpal Nandi Utpal Nandi Zabeer Ahmed Zabeer Ahmed Ajay Kumar Ajay Kumar |
| author_facet | Dilpreet Kour Dilpreet Kour Parul Khajuria Parul Khajuria Kuhu Sharma Kuhu Sharma Alpa Sharma Alpa Sharma Ankita Sharma Ankita Sharma Syed Mudassir Ali Priya Wazir P. Ramajayan P. Ramajayan Sanghapal D. Sawant Sanghapal D. Sawant Sanghapal D. Sawant Utpal Nandi Utpal Nandi Zabeer Ahmed Zabeer Ahmed Ajay Kumar Ajay Kumar |
| author_sort | Dilpreet Kour |
| collection | DOAJ |
| description | Background and AimAlzheimer’s disease (AD) progresses with Aβ plaque deposition and neuroinflammation. Given the complexity of AD pathology, single-target therapies have frequently failed in clinical trials. We hypothesized that a multitarget approach could yield better therapeutic outcomes. To this end, we identified isobavachalcone (IBC), a natural compound with dual pharmacological activity in reducing Aβ plaques and neuroinflammation.Experimental ProcedurePrimary astrocytes were isolated from 3 to 4 days old C57BL/6J mice pups for in-vitro assays, while in-vivo studies were conducted on 5x-FAD mice. Protein alterations were evaluated using ELISA, western blotting, immunocytochemistry, and immunohistochemistry. Behavioral analyses included the radial arm maze, open field, and rotarod tests. Data from all in vitro and in vivo experiments were analyzed by using one-way ANOVA and post-hoc Bonferroni tests.ResultsIn-vitro analyses in astrocytes demonstrated that IBC at 5 and 10 μM concentrations induce AMPK phosphorylation through CAMKK2, promoting autophagy and inhibiting the NLRP3 inflammasome in primary astrocytes. IBC-treated astrocytes exhibited significant clearance of extracellular amyloid beta. Mechanistic studies highlighted autophagy as a key factor in reducing both NLRP3 inflammasome activity and Aβ levels. Two months of treatment of 5x-FAD mice with IBC at 25 and 50 mg/kg significantly improved cognitive functions, as evidenced by enhanced memory and motor performance in behavioral tests. Subsequent brain tissue analysis revealed that IBC upregulated autophagic proteins to reduce the brain’s amyloid beta levels, resulting in decreased expression of neuroinflammation markers.ConclusionIBC effectively ameliorates AD pathology through autophagy-mediated clearance of Aβ and suppressing neuroinflammation in 5x-FAD mice. |
| format | Article |
| id | doaj-art-65fde869de6f4951b3a12932a84c0b2a |
| institution | Kabale University |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj-art-65fde869de6f4951b3a12932a84c0b2a2025-08-20T03:42:53ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-03-011610.3389/fphar.2025.15253641525364Isobavachalcone ameliorates Alzheimer disease pathology by autophagy-mediated clearance of amyloid beta and inhibition of NLRP3 inflammasome in primary astrocytes and 5x-FAD miceDilpreet Kour0Dilpreet Kour1Parul Khajuria2Parul Khajuria3Kuhu Sharma4Kuhu Sharma5Alpa Sharma6Alpa Sharma7Ankita Sharma8Ankita Sharma9Syed Mudassir Ali10Priya Wazir11P. Ramajayan12P. Ramajayan13Sanghapal D. Sawant14Sanghapal D. Sawant15Sanghapal D. Sawant16Utpal Nandi17Utpal Nandi18Zabeer Ahmed19Zabeer Ahmed20Ajay Kumar21Ajay Kumar22Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, IndiaAcademy of Scientific and Innovative Research (AcSIR), Ghaziabad, IndiaPharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, IndiaAcademy of Scientific and Innovative Research (AcSIR), Ghaziabad, IndiaPharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, IndiaAcademy of Scientific and Innovative Research (AcSIR), Ghaziabad, IndiaAcademy of Scientific and Innovative Research (AcSIR), Ghaziabad, IndiaNatural Products and Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, IndiaPharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, IndiaAcademy of Scientific and Innovative Research (AcSIR), Ghaziabad, IndiaPharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, IndiaPharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, IndiaPharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, IndiaAcademy of Scientific and Innovative Research (AcSIR), Ghaziabad, IndiaAcademy of Scientific and Innovative Research (AcSIR), Ghaziabad, IndiaNatural Products and Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, IndiaOrganic Chemsitry Division, CSIR-National Chemical Laboratory, Pune, IndiaPharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, IndiaAcademy of Scientific and Innovative Research (AcSIR), Ghaziabad, IndiaPharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, IndiaAcademy of Scientific and Innovative Research (AcSIR), Ghaziabad, IndiaPharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, IndiaAcademy of Scientific and Innovative Research (AcSIR), Ghaziabad, IndiaBackground and AimAlzheimer’s disease (AD) progresses with Aβ plaque deposition and neuroinflammation. Given the complexity of AD pathology, single-target therapies have frequently failed in clinical trials. We hypothesized that a multitarget approach could yield better therapeutic outcomes. To this end, we identified isobavachalcone (IBC), a natural compound with dual pharmacological activity in reducing Aβ plaques and neuroinflammation.Experimental ProcedurePrimary astrocytes were isolated from 3 to 4 days old C57BL/6J mice pups for in-vitro assays, while in-vivo studies were conducted on 5x-FAD mice. Protein alterations were evaluated using ELISA, western blotting, immunocytochemistry, and immunohistochemistry. Behavioral analyses included the radial arm maze, open field, and rotarod tests. Data from all in vitro and in vivo experiments were analyzed by using one-way ANOVA and post-hoc Bonferroni tests.ResultsIn-vitro analyses in astrocytes demonstrated that IBC at 5 and 10 μM concentrations induce AMPK phosphorylation through CAMKK2, promoting autophagy and inhibiting the NLRP3 inflammasome in primary astrocytes. IBC-treated astrocytes exhibited significant clearance of extracellular amyloid beta. Mechanistic studies highlighted autophagy as a key factor in reducing both NLRP3 inflammasome activity and Aβ levels. Two months of treatment of 5x-FAD mice with IBC at 25 and 50 mg/kg significantly improved cognitive functions, as evidenced by enhanced memory and motor performance in behavioral tests. Subsequent brain tissue analysis revealed that IBC upregulated autophagic proteins to reduce the brain’s amyloid beta levels, resulting in decreased expression of neuroinflammation markers.ConclusionIBC effectively ameliorates AD pathology through autophagy-mediated clearance of Aβ and suppressing neuroinflammation in 5x-FAD mice.https://www.frontiersin.org/articles/10.3389/fphar.2025.1525364/fullAlzheimer diseaseamyloid betaautophagyisobavachalconeneuroinflammationNLRP3 inflammasome |
| spellingShingle | Dilpreet Kour Dilpreet Kour Parul Khajuria Parul Khajuria Kuhu Sharma Kuhu Sharma Alpa Sharma Alpa Sharma Ankita Sharma Ankita Sharma Syed Mudassir Ali Priya Wazir P. Ramajayan P. Ramajayan Sanghapal D. Sawant Sanghapal D. Sawant Sanghapal D. Sawant Utpal Nandi Utpal Nandi Zabeer Ahmed Zabeer Ahmed Ajay Kumar Ajay Kumar Isobavachalcone ameliorates Alzheimer disease pathology by autophagy-mediated clearance of amyloid beta and inhibition of NLRP3 inflammasome in primary astrocytes and 5x-FAD mice Frontiers in Pharmacology Alzheimer disease amyloid beta autophagy isobavachalcone neuroinflammation NLRP3 inflammasome |
| title | Isobavachalcone ameliorates Alzheimer disease pathology by autophagy-mediated clearance of amyloid beta and inhibition of NLRP3 inflammasome in primary astrocytes and 5x-FAD mice |
| title_full | Isobavachalcone ameliorates Alzheimer disease pathology by autophagy-mediated clearance of amyloid beta and inhibition of NLRP3 inflammasome in primary astrocytes and 5x-FAD mice |
| title_fullStr | Isobavachalcone ameliorates Alzheimer disease pathology by autophagy-mediated clearance of amyloid beta and inhibition of NLRP3 inflammasome in primary astrocytes and 5x-FAD mice |
| title_full_unstemmed | Isobavachalcone ameliorates Alzheimer disease pathology by autophagy-mediated clearance of amyloid beta and inhibition of NLRP3 inflammasome in primary astrocytes and 5x-FAD mice |
| title_short | Isobavachalcone ameliorates Alzheimer disease pathology by autophagy-mediated clearance of amyloid beta and inhibition of NLRP3 inflammasome in primary astrocytes and 5x-FAD mice |
| title_sort | isobavachalcone ameliorates alzheimer disease pathology by autophagy mediated clearance of amyloid beta and inhibition of nlrp3 inflammasome in primary astrocytes and 5x fad mice |
| topic | Alzheimer disease amyloid beta autophagy isobavachalcone neuroinflammation NLRP3 inflammasome |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2025.1525364/full |
| work_keys_str_mv | AT dilpreetkour isobavachalconeamelioratesalzheimerdiseasepathologybyautophagymediatedclearanceofamyloidbetaandinhibitionofnlrp3inflammasomeinprimaryastrocytesand5xfadmice AT dilpreetkour isobavachalconeamelioratesalzheimerdiseasepathologybyautophagymediatedclearanceofamyloidbetaandinhibitionofnlrp3inflammasomeinprimaryastrocytesand5xfadmice AT parulkhajuria isobavachalconeamelioratesalzheimerdiseasepathologybyautophagymediatedclearanceofamyloidbetaandinhibitionofnlrp3inflammasomeinprimaryastrocytesand5xfadmice AT parulkhajuria isobavachalconeamelioratesalzheimerdiseasepathologybyautophagymediatedclearanceofamyloidbetaandinhibitionofnlrp3inflammasomeinprimaryastrocytesand5xfadmice AT kuhusharma isobavachalconeamelioratesalzheimerdiseasepathologybyautophagymediatedclearanceofamyloidbetaandinhibitionofnlrp3inflammasomeinprimaryastrocytesand5xfadmice AT kuhusharma isobavachalconeamelioratesalzheimerdiseasepathologybyautophagymediatedclearanceofamyloidbetaandinhibitionofnlrp3inflammasomeinprimaryastrocytesand5xfadmice AT alpasharma isobavachalconeamelioratesalzheimerdiseasepathologybyautophagymediatedclearanceofamyloidbetaandinhibitionofnlrp3inflammasomeinprimaryastrocytesand5xfadmice AT alpasharma isobavachalconeamelioratesalzheimerdiseasepathologybyautophagymediatedclearanceofamyloidbetaandinhibitionofnlrp3inflammasomeinprimaryastrocytesand5xfadmice AT ankitasharma isobavachalconeamelioratesalzheimerdiseasepathologybyautophagymediatedclearanceofamyloidbetaandinhibitionofnlrp3inflammasomeinprimaryastrocytesand5xfadmice AT ankitasharma isobavachalconeamelioratesalzheimerdiseasepathologybyautophagymediatedclearanceofamyloidbetaandinhibitionofnlrp3inflammasomeinprimaryastrocytesand5xfadmice AT syedmudassirali isobavachalconeamelioratesalzheimerdiseasepathologybyautophagymediatedclearanceofamyloidbetaandinhibitionofnlrp3inflammasomeinprimaryastrocytesand5xfadmice AT priyawazir isobavachalconeamelioratesalzheimerdiseasepathologybyautophagymediatedclearanceofamyloidbetaandinhibitionofnlrp3inflammasomeinprimaryastrocytesand5xfadmice AT pramajayan isobavachalconeamelioratesalzheimerdiseasepathologybyautophagymediatedclearanceofamyloidbetaandinhibitionofnlrp3inflammasomeinprimaryastrocytesand5xfadmice AT pramajayan isobavachalconeamelioratesalzheimerdiseasepathologybyautophagymediatedclearanceofamyloidbetaandinhibitionofnlrp3inflammasomeinprimaryastrocytesand5xfadmice AT sanghapaldsawant isobavachalconeamelioratesalzheimerdiseasepathologybyautophagymediatedclearanceofamyloidbetaandinhibitionofnlrp3inflammasomeinprimaryastrocytesand5xfadmice AT sanghapaldsawant isobavachalconeamelioratesalzheimerdiseasepathologybyautophagymediatedclearanceofamyloidbetaandinhibitionofnlrp3inflammasomeinprimaryastrocytesand5xfadmice AT sanghapaldsawant isobavachalconeamelioratesalzheimerdiseasepathologybyautophagymediatedclearanceofamyloidbetaandinhibitionofnlrp3inflammasomeinprimaryastrocytesand5xfadmice AT utpalnandi isobavachalconeamelioratesalzheimerdiseasepathologybyautophagymediatedclearanceofamyloidbetaandinhibitionofnlrp3inflammasomeinprimaryastrocytesand5xfadmice AT utpalnandi isobavachalconeamelioratesalzheimerdiseasepathologybyautophagymediatedclearanceofamyloidbetaandinhibitionofnlrp3inflammasomeinprimaryastrocytesand5xfadmice AT zabeerahmed isobavachalconeamelioratesalzheimerdiseasepathologybyautophagymediatedclearanceofamyloidbetaandinhibitionofnlrp3inflammasomeinprimaryastrocytesand5xfadmice AT zabeerahmed isobavachalconeamelioratesalzheimerdiseasepathologybyautophagymediatedclearanceofamyloidbetaandinhibitionofnlrp3inflammasomeinprimaryastrocytesand5xfadmice AT ajaykumar isobavachalconeamelioratesalzheimerdiseasepathologybyautophagymediatedclearanceofamyloidbetaandinhibitionofnlrp3inflammasomeinprimaryastrocytesand5xfadmice AT ajaykumar isobavachalconeamelioratesalzheimerdiseasepathologybyautophagymediatedclearanceofamyloidbetaandinhibitionofnlrp3inflammasomeinprimaryastrocytesand5xfadmice |