Liraglutide Protects Against Brain Amyloid-β1–42 Accumulation in Female Mice with Early Alzheimer’s Disease-Like Pathology by Partially Rescuing Oxidative/Nitrosative Stress and Inflammation
Abstract
:1. Introduction
2. Results
2.1. Effect of Liraglutide Treatment on Brain and Peripheral Features in Female Mice
2.2. Liraglutide Partially Normalizes Brain Levels of Estradiol and GLP-1-Related Signaling in Female Mice with Early AD-Like Pathology
2.3. Liraglutide Promotes Brain Glucose Metabolism via the Oxidative Branch of the Pentose Phosphate Pathway in Female Mice with Early AD-Like Pathology
2.4. Liraglutide Partially Rescues Brain Oxidative/Nitrosative Stress Markers in Female Mice with Early AD-Like Pathology
2.5. Liraglutide Partially Attenuates the Altered Mitochondrial Fission/Fusion Proteins in Female Mice with Early AD-Like Pathology
3. Discussion
4. Material and Methods
4.1. Materials
4.2. Animal Housing and Treatment
4.3. Body and Brain Weight
4.4. Collection of Peripheral Blood and Routine Biochemical Analyses
4.5. Isolation and Preparation of Brain Cortical Homogenates
4.6. Evaluation of AD Pathological Hallmarks
4.7. Behavioral Analyses
4.7.1. Open Field Behavior Test
4.7.2. Y-maze Behavior Test
4.7.3. Morris Water Maze Test
4.8. Evaluation of Inflammation Markers
4.9. Evaluation of Brain Cortical Hormones’ Levels
4.10. Assessment of Brain Cortical PKA Activity
4.11. Assessment of Brain Cortical Glucose Levels
4.12. Determination of Brain Markers for Glycolysis and Pentose Phosphate Pathway
4.13. Evaluation of Oxidative/Nitrosative Stress Markers
4.14. Western Blot Analyses
4.15. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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WT | 3xTg-AD | 3xTg-AD + Lira | |
---|---|---|---|
Body weight (g) | 29.1 ± 1.2 (n = 10) (95% CI: 26.3–31.8) | 23.3 ± 0.6 **** (n = 12) (95% CI: 22.1–24.6) | 23.3 ± 0.4 **** (n = 14) (95% CI: 22.6–24.1) |
Brain weight (g) | 0.5 ± 0.01 (n = 7) (95% CI: 0.45–0.51) | 0.4 ± 0.03 (n = 8) (95% CI: 0.36–0.52) | 0.5 ± 0.03 (n = 10) (95% CI: 0.42–0.54) |
HbA1c (%) | 4.3 ± 0.2 (n = 10) (95% CI: 3.74–4.84) | 4.4 ± 0.1 (n = 11) (95% CI: 4.17–4.65) | 4.4 ± 0.1 (n = 12) (95% CI: 4.13–4.57) |
Occasional glycemia (mg glucose/dL blood) | 132.8 ± 3.3 (n = 9) (95% CI: 125.2–140.3) | 121.2 ± 7.3 (n = 12) (95% CI: 105.2–137.2) | 128.1 ± 10.5 (n = 14) (95% CI: 105.6–150.7) |
Fasting glycemia (mg glucose/dL blood) | 126.4 ± 4.7 (n = 9) (95% CI: 115.6–137.7) | 110.3 ± 8.2 (n = 12) (95% CI: 92.4–128.3) | 127.6 ± 6.5 p = 0.073 (n = 14) (95% CI: 113.7–141.6) |
Fasting insulin levels (ng/mL plasma) | 3.5 ± 1.5 (n = 10) (95% CI: 0.07–6.97) | 2.5 ± 0.8 (n = 11) (95% CI: 0.72–4.23) | 1.3 ± 0.4 (n = 11) (95% CI: 0.56–2.13) |
HOMA-IR | 30.2 ± 13.1 (n = 10) (95% CI: 0.7–59.8) | 15.2 ± 5.0 (n = 11) (95% CI: 4.05–26.37) | 11.3 ± 3.1 (n = 11) (95% CI: 4.37–18.26) |
HOMA-β | 217.5 ± 124.23 (n = 8) (95% CI: −76.25–511.26) | 262.1 ± 93.01 (n = 9) (95% CI: 47.60–476.5) | 170 ± 43.33 (n = 10) (95% CI: 72–268) |
Estradiol levels (pg/mL plasma) | 184.1 ± 15.1 (n = 7) (95% CI: 147.2–220.9) | 230.8 ± 24.3 p = 0.07 (n = 6) (95% CI: 168.3–293.3) | 244.9 ± 9.5 p = 0.023 (n = 6) (95% CI: 220.3–269.4) |
C-Reactive Protein levels (ng/mL plasma) | 31.9 ± 6.1 (n = 6) (95% CI: 16.25–47.51) | 74.3 ± 17.6 * (n = 6) (95% CI: 29.10–119.4) | 60.8 ± 10.7 (n = 7) (95% CI: 34.53–86.98) |
IL-10 levels (pg/mL plasma) | 551.5 ± 134.6 (n = 7) (95% CI: 222.1–880.9) | 364.6 ± 81.6 (n = 6) (95% CI: 154.8–574.3) | 494.3 ± 54.5 (n = 7) (95% CI: 361.1–627.6) |
IL-1β levels (pg/mL plasma) | 43.2 ± 12.3 (n = 6) (95% CI: 11.66–74.66) | 821.6 ± 400.7 ** (n = 6) (95% CI: −208.3–1852) | 355.4 ± 159.3 p = 0.051 (n = 7) (95% CI: −34.38–745.3) |
WT | 3xTg-AD | 3xTg-AD + Lira | |
---|---|---|---|
Estradiol levels (pg/mg protein) | 5.62 ± 1.19 (n = 5) (95% CI: 2.31–8.93) | 15.2 ± 2.7 * (n = 6) (95% CI: 8.27–22.11) | 12.2 ± 3.3 (n = 5) (95% CI: 3.1–21.24) |
GLP-1 levels (pg/mg protein) | 5.9 ± 2.5 (n = 5) (95% CI: −1.14–12.94) | 21.1 ± 6.5 * (n = 6) (95% CI: 4.52–37.74) | 15.0 ± 2.8 (n = 5) (95% CI: 7.29–22.76) |
Active PKA kinase (ng active PKA/mg protein) | 0.01 ± 0.004 (n = 6) (95% CI: −0.0005–0.02) | 0.001 ± 0.0004 ** (n = 6) (95% CI: 0.0001–0.002) | 0.009 ± 0.005 (n = 5) (95% CI: −0.0048–0.022) |
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Duarte, A.I.; Candeias, E.; Alves, I.N.; Mena, D.; Silva, D.F.; Machado, N.J.; Campos, E.J.; Santos, M.S.; Oliveira, C.R.; Moreira, P.I. Liraglutide Protects Against Brain Amyloid-β1–42 Accumulation in Female Mice with Early Alzheimer’s Disease-Like Pathology by Partially Rescuing Oxidative/Nitrosative Stress and Inflammation. Int. J. Mol. Sci. 2020, 21, 1746. https://doi.org/10.3390/ijms21051746
Duarte AI, Candeias E, Alves IN, Mena D, Silva DF, Machado NJ, Campos EJ, Santos MS, Oliveira CR, Moreira PI. Liraglutide Protects Against Brain Amyloid-β1–42 Accumulation in Female Mice with Early Alzheimer’s Disease-Like Pathology by Partially Rescuing Oxidative/Nitrosative Stress and Inflammation. International Journal of Molecular Sciences. 2020; 21(5):1746. https://doi.org/10.3390/ijms21051746
Chicago/Turabian StyleDuarte, Ana I., Emanuel Candeias, Inês N. Alves, Débora Mena, Daniela F. Silva, Nuno J. Machado, Elisa J. Campos, Maria S. Santos, Catarina R. Oliveira, and Paula I. Moreira. 2020. "Liraglutide Protects Against Brain Amyloid-β1–42 Accumulation in Female Mice with Early Alzheimer’s Disease-Like Pathology by Partially Rescuing Oxidative/Nitrosative Stress and Inflammation" International Journal of Molecular Sciences 21, no. 5: 1746. https://doi.org/10.3390/ijms21051746