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

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 PPAR alpha. This study underlines the importance of Hex in inducing the expression of brain-derived neurotrophic factor (IMF) from hippocampal neurons via PPAR alpha. The level of Hex was lower in the hippocampi of SXFAD 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 SXFAD mice. However, oral Hex remained unable to stimulate hippocampal plasticity and improve cognitive behaviors in 5XFAD(P)(par alpha-null) and 5XFAD(Ppar)(alpha-Delta Hippo) mice, indicating an essential role of hippocampal PPAR alpha 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.