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 3

Hex promotes synaptic functions in the hippocampi of 5XFAD mice.

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Hex promotes synaptic functions in the hippocampi of 5XFAD mice. (A) 5XF...
(A) 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 treatment, PSD95 protein levels were investigated by immunostaining hippocampal tissue harvested from hippocampi of NTG and vehicle fed- and Hex-fed 5XFAD mice with antibodies against neuronal marker MAP2 (green) and PSD95 (red). Scale bars: 50 μm. (B) Colocalization of PSD95 with MAP2 was analyzed by quantifying PSD95 and MAP2 immunoreactive puncta using ImageJ. For quantification, 2 sections per mice (n = 6/group) were used. Results are shown as mean ± SEM. One-way ANOVA [PSD95 puncta: F(2,33) = 39.712, 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. (C) AMPA-dependent and (D) NMDA-dependent calcium currents measured in the hippocampal slices of NTG, vehicle-fed, and Hex-fed 5XFAD mice. The arrow indicates the application of AMPA and NMDA in the assay. To nullify the secondary involvement of AMPA receptor in NMDA-dependent calcium currents, hippocampal slices were treated with NMDA together with NASPM (Ca2+-permeable AMPA antagonist), followed by the recording of calcium influx. Similarly, AMPA-dependent calcium influx was measured in the presence of N20C (noncompetitive NMDA open-channel blocker). Calcium influx was monitored for 300 repeats in a PerkinElmer VICTOR X2 fluorimeter. Results represent the mean of 3 independent experiments.