Estradiol Prevents Amyloid Beta-Induced Mitochondrial Dysfunction and Neurotoxicity in Alzheimer’s Disease via AMPK-Dependent Suppression of NF-κB Signaling
Abstract
1. Introduction
2. Results
2.1. E2 Activates AMPK in a Dose- and Time-Dependent Manner and Enhances PGC-1α Levels
2.2. E2 Enhances Mitochondrial Respiration and Suppresses NF-κB Subunit Expression
2.3. Aβ Suppresses AMPK Activation, Reduces PGC-1α Levels, and Impairs Mitochondrial Function
2.4. Aβ Activates NF-κB and Reduces Cell Viability
2.5. E2 Pretreatment Rescues Aβ-Induced Mitochondrial Dysfunction, Restores AMPK and PGC-1α Signaling, and Preserves Mitochondrial Electron Transport Chain Integrity
2.6. E2 Pretreatment Suppresses Aβ-Induced Neuroinflammation by Inhibiting NF-κB and Inflammasome Activity
2.7. E2 Pretreatment Rescues Aβ-Induced Cytotoxicity and Preserves Neuronal Viability During Prolonged Exposure
2.8. AMPK Mediates E2’s Neuroprotective Effects Against Aβ-Induced Mitochondrial Dysfunction and Neurotoxicity
2.9. E2 Acts via AMPK to Suppress Aβ-Induced NF-κB Subunit Expression
2.10. NF-κB Inhibition Partially Rescues Mitochondrial Dysfunction but Fails to Prevent Aβ-Induced Cytotoxicity
3. Discussion
4. Materials and Methods
4.1. Cell Culture
4.2. Amyloid Beta Preparation
4.3. Quantitative Western Blotting
4.4. Seahorse Assay to Measure Mitochondrial Respiration
4.5. MTT Assay
4.6. LDH Assay
4.7. NF-κB p65 Activation Assay
4.8. Measurement of Caspase-1 Activity
4.9. ATP Measurement
4.10. ELISA
4.11. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
AD | Alzheimer’s disease |
AMPK | AMP-activated protein kinase |
ATP | Adenosine triphosphate |
Aβ | Amyloid-beta |
CC | Compound C (AMPK inhibitor) |
CNS | Central nervous system |
DAMPs | Damage-associated molecular patterns |
DMSO | Dimethyl sulfoxide |
E2 | 17β-estradiol |
ELISA | Enzyme-linked immunosorbent assay |
ER | Estrogen receptor |
ETC | Electron transport chain |
FBS | Fetal bovine serum |
GPER | G-protein coupled estrogen receptor |
HASMCs | Human aortic smooth muscle cells |
HFIP | Hexafluoroisopropanol |
IL | Interleukin |
JAK/STAT | Janus kinase/signal transducer and activator of transcription |
LDH | Lactate dehydrogenase |
MAPK | Mitogen-activated protein kinase |
mtDNA | Mitochondrial DNA |
NFTs | Neurofibrillary tangles |
NF-κB | Nuclear factor kappa-light-chain enhancer of activated B cells |
NRF1/2 | Nuclear respiratory factor 1/2 |
OCR | Oxygen consumption rate |
OXPHOS | Oxidative phosphorylation |
pAMPK | Phosphorylated AMPK |
PGC-1α | Peroxisome proliferator-activated receptor; Gamma coactivator 1-alpha |
RASMCs | Rat aortic smooth muscle cells |
SDS-PAGE | Sodium dodecyl sulfate–polyacrylamide gel electrophoresis |
SIRT1 | Sirtuin 1 |
T-AMPK | Total AMPK |
TFAM | Mitochondrial transcription factor A |
TNFα | Tumor necrosis factor alpha |
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Mishra, P.; Esfahani, E.K.; Fernyhough, P.; Albensi, B.C. Estradiol Prevents Amyloid Beta-Induced Mitochondrial Dysfunction and Neurotoxicity in Alzheimer’s Disease via AMPK-Dependent Suppression of NF-κB Signaling. Int. J. Mol. Sci. 2025, 26, 6203. https://doi.org/10.3390/ijms26136203
Mishra P, Esfahani EK, Fernyhough P, Albensi BC. Estradiol Prevents Amyloid Beta-Induced Mitochondrial Dysfunction and Neurotoxicity in Alzheimer’s Disease via AMPK-Dependent Suppression of NF-κB Signaling. International Journal of Molecular Sciences. 2025; 26(13):6203. https://doi.org/10.3390/ijms26136203
Chicago/Turabian StyleMishra, Pranav, Ehsan K. Esfahani, Paul Fernyhough, and Benedict C. Albensi. 2025. "Estradiol Prevents Amyloid Beta-Induced Mitochondrial Dysfunction and Neurotoxicity in Alzheimer’s Disease via AMPK-Dependent Suppression of NF-κB Signaling" International Journal of Molecular Sciences 26, no. 13: 6203. https://doi.org/10.3390/ijms26136203
APA StyleMishra, P., Esfahani, E. K., Fernyhough, P., & Albensi, B. C. (2025). Estradiol Prevents Amyloid Beta-Induced Mitochondrial Dysfunction and Neurotoxicity in Alzheimer’s Disease via AMPK-Dependent Suppression of NF-κB Signaling. International Journal of Molecular Sciences, 26(13), 6203. https://doi.org/10.3390/ijms26136203