Upregulation of BDNF and hippocampal functions by a hippocampal ligand of PPARα
Dhruv Patel, Avik Roy, Sumita Raha, Madhuchhanda Kundu, Frank J. Gonzalez, Kalipada Pahan
Dhruv Patel, Avik Roy, Sumita Raha, Madhuchhanda Kundu, Frank J. Gonzalez, Kalipada Pahan
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Research Article Neuroscience

Upregulation of BDNF and hippocampal functions by a hippocampal ligand of PPARα

Abstract

Discovery strategies commonly focus on the identification of chemical libraries or natural products, but the modulation of endogenous ligands offers a much better therapeutic strategy due to their low adverse potential. Recently, we found that hexadecanamide (Hex) is present in hippocampal nuclei of normal mice as an endogenous ligand of PPARα. This study underlines the importance of Hex in inducing the expression of brain-derived neurotrophic factor (BDNF) from hippocampal neurons via PPARα. The level of Hex was lower in the hippocampi of 5XFAD mice as compared with that in non-Tg mice. Oral administration of Hex increased the level of this molecule in the hippocampus to stimulate BDNF and its downstream plasticity-associated molecules, promote synaptic functions in the hippocampus, and improve memory and learning in 5XFAD mice. However, oral Hex remained unable to stimulate hippocampal plasticity and improve cognitive behaviors in 5XFADPparα-null and 5XFADPparα-ΔHippo mice, indicating an essential role of hippocampal PPARα in Hex-mediated improvement in hippocampal functions. This is the first demonstration to our knowledge of protection of hippocampal functions by oral administration of a hippocampus-based drug, suggesting that Hex may be explored for therapeutic intervention in AD.

Authors

Dhruv Patel, Avik Roy, Sumita Raha, Madhuchhanda Kundu, Frank J. Gonzalez, Kalipada Pahan

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Figure 2

Hex upregulates BDNF and other hippocampal plasticity–associated proteins in the hippocampi of 5XFAD mice.

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Hex upregulates BDNF and other hippocampal plasticity–associated protein...
5XFAD mice (n = 6/group; 6–7 months old) were treated orally with Hex (5 mg/kg/d) or vehicle (0.1% methyl cellulose) for 1 month. Untreated non-Tg (NTG) mice (n = 6) were used as control. Following 1 month of Hex treatment, the mRNA expression of several plasticity-associated genes was analyzed by real-time PCR, followed by gene array analysis. GAPDH was used as an endogenous control. (A) Heatmap showing relative expression of differentially regulated plasticity genes in hippocampi of NTG or Hex-fed 5XFAD mice compared with that of vehicle-fed 5XFAD mice. (B) Venn diagram summarizing the numbers of differentially regulated plasticity genes. Relative expression greater than 2 was considered statistically significant. (C) Similarly, following 1 month of Hex treatment, protein levels in hippocampal homogenates of selected plasticity-associated molecules (BDNF, PSD95, GluR1, and NR2A) were analyzed by immunoblot analysis. β-Actin was used as a loading control. Uncropped Western blot images are shown in Supplemental Figure 6. Relative densities of BDNF (D), PSD95 (G), GLUR1 (H), and NR2A (I) immunoblots compared with that of β-actin were calculated by ImageJ. Results are shown as mean ± SEM. One-way ANOVA [BDNF protein, F(2,15) = 6.5000, P = 0.009; PSD95 protein, F(2,15) = 23.977, P < 0.001; GLUR1 protein, F(2,15) = 74.063, P < 0.001; NR2A protein, F(2,15) = 19.624, P < 0.001], followed by Bonferroni’s multiple comparisons test was used to assess significance of the mean; *P < 0.05 vs. vehicle-fed 5XFAD; **P < 0.01, ***P < 0.001 vs. vehicle-fed 5XFAD. Hippocampal sections were also double labeled for MAP2 (green) and BDNF (red) (E). Scale bars: 50 μm. (F) MFI of hippocampal BDNF was calculated using ImageJ. For quantification, 2 sections per mice (n = 6/group) were used. Results are shown as mean ± SEM. One-way ANOVA [BDNF MFI: F(2,33) = 115.77, P < 0.001] followed by Bonferroni’s multiple comparisons test was used to assess significance of the mean; **P < 0.01 vs. vehicle-fed 5XFAD.