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

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

doi:10.1172/jci.insight.136654

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.

Highlights

Alzheimer’s disease (AD) is an irreversible and a progressive form of dementia that slowly destroys cognitive functions; it is severe enough to interfere with activities of daily living
Since brain-derived neurotrophic factor (BDNF) is known for its ability to modulate hippocampal plasticity, we wanted to explore the role of Hex in regulating the expression of hippocampal BDNF
Immunoblot analyses (Figure 1C), densitometric analyses (Figure 1D), and immunofluorescence analyses (Figure 1E) further corroborated the finding that lowdose (2 μM) Hex significantly stimulated the level of BDNF in hippocampal neurons

Summary

Introduction

Alzheimer’s disease (AD) is an irreversible and a progressive form of dementia that slowly destroys cognitive functions; it is severe enough to interfere with activities of daily living. Accumulating evidences link AD pathology with reduced BDNF levels in the serum [2] and in the cognition-related structures, such the as hippocampus and frontal cortex [3]. BDNF is a prominent neurotrophin that regulates many of the hippocampus-based biological processes that include maintenance and survival of hippocampal neurons [4], promoting hippocampal dendritic spine density and morphology [5], and enhancing hippocampal neurogenesis [6]. Considering its essential role in providing trophic support to degenerating neurons and promoting postsynaptic functions, BDNF has, gained an enormous attention as a promising therapeutic target in countering AD pathology. Current BDNF-based therapeutics are not that effective in delivering desirable relief to patients with AD. Enhancing the production of BDNF in vivo in the hippocampus using safer and effective approaches is presently an important area of research

Methods

Results

Conclusion