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 5

Hex upregulates BDNF and PSD95 in the hippocampi of 5XFAD mice via PPARα.

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Hex upregulates BDNF and PSD95 in the hippocampi of 5XFAD mice via PPARα...
(A) 5XFAD and 5XFADPparα-null 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 followed by analysis of BDNF and PSD95 proteins by immunoblot. Uncropped Western blot images are shown in Supplemental Figure 6. (B) Relative density of BDNF and PSD95 protein expressions compared with β-actin was calculated by ImageJ. Results are shown as mean ± SEM. One-way ANOVA followed by Bonferroni’s multiple comparisons test was used to assess the significance of the mean; **P < 0.01 vs. vehicle-fed 5XFAD, nsP > 0.05 vs. vehicle-fed 5XFAD. (C) Hippocampal sections were double labeled with either BDNF (red) plus MAP2 (green) or PSD95 (red) plus MAP2 (green). Scale bar: 50 μm. Raw images are shown in Supplemental Figure 6. (D) MFI of hippocampal BDNF was quantified in 2 sections of each of 6 mice per group. One-way ANOVA [BDNF MFI: F(4,55) = 114.28, P < 0.001], followed by Bonferroni’s multiple comparisons test was used; **P < 0.01 vs. vehicle-fed 5XFAD, nsP > 0.05 vs. vehicle-fed 5XFAD. (E) Colocalization of PSD95 with MAP2 was analyzed by quantifying PSD95 and MAP2 immunoreactive puncta using ImageJ. For quantification, 2 sections per mice (n = 6 per group) was used. Results are shown as mean ± SEM. One-way ANOVA [PSD95 puncta: F(4,55) = 52.569, P < 0.001], followed by Bonferroni’s multiple comparisons test was used to assess the significance of the mean, **P < 0.01 vs. vehicle-fed 5XFAD, nsP > 0.05 vs. vehicle-fed 5XFAD.