Upregulation of BDNF and hippocampal functions by a hippocampal ligand of PPARα
Dhruv Patel, … , Frank J. Gonzalez, Kalipada Pahan
Dhruv Patel, … , Frank J. Gonzalez, Kalipada Pahan
Published April 21, 2020
Citation Information: JCI Insight. 2020;5(10):e136654. https://doi.org/10.1172/jci.insight.136654.
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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 1

Hex upregulates BDNF and other members of the neurotrophin family in the primary hippocampal neurons.

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Hex upregulates BDNF and other members of the neurotrophin family in the...
Primary hippocampal neurons derived from E18 C57BL6 mice pups were treated at 14 days in vitro (DIV) with increasing doses of Hex (μM) for 5 hours, followed by mRNA expression analyses of different members of the neurotrophin family (Bdnf, NT3, and NT4) along with their receptors (TrkB and P75NTR) using semiquantitative RT-PCR (A) and quantitative real-time PCR (B). Expression of GAPDH mRNA was used as loading control. Results are shown as mean ± SD, and 1-way ANOVA [Bdnf mRNA, F(2,6) = 17.990, P = 0.003; NT3 mRNA, F(2,6) = 18.058; NT4 mRNA, F(2,6) = 3.9702, P = 0.080; TrkB mRNA, F(2,6) = 27.393, P < 0.001; P75NTR mRNA, F(2,6) = 3.6634; P = 0.091] followed by Bonferroni’s multiple comparisons test, was used to assess significance of the mean; *P < 0.05, **P < 0.01 vs. control. Following dose-dependent treatment with Hex (μM) for 12 hours, the protein expression of BDNF (C), NT3 (F), and TrkB (I) was investigated in the primary hippocampal neurons by immunoblot analysis (see complete unedited blots in the supplemental material). Relative densities of BDNF (D), NT3 (G), and TrkB (J) protein expressions compared with β-actin were calculated by ImageJ. Results are shown as mean ± SD and 1-way ANOVA [BDNF protein, F(2,6) = 8.9312, P = 0.016; NT3 protein, F(2,6) = 52.019, P < 0.001; TrkB protein, F(2,6) = 8.7881, P = 0.02] followed by Bonferroni’s multiple comparisons test was used to assess significance of the mean; *P < 0.05, **P < 0.01 vs. control. BDNF and NT3 protein levels were also investigated by immunostaining Hex-treated primary hippocampal neurons with neuronal marker MAP2 (green) and BDNF (red) (E) or MAP2 (green) and NT3 (red) (H). Scale bars: 20 μm.