Oleamide, a Sleep-Inducing Supplement, Upregulates Doublecortin in Hippocampal Progenitor Cells via PPARα

J Alzheimers Dis. 2021;84(4):1747-1762. doi: 10.3233/JAD-215124.


Background: Doublecortin (DCX), a microtubule associated protein, has emerged as a central biomarker of hippocampal neurogenesis. However, molecular mechanisms by which DCX is regulated are poorly understood.

Objective: Since sleep is involved with the acquisition of memory and oleamide or 9-Octadecenamide (OCT) is a sleep-inducing supplement in human, we examined whether OCT could upregulate DCX in hippocampal progenitor cells (HPCs).

Methods: We employed real-time PCR, western blot, immunostaining, chromatin immunoprecipitation, lentiviral transduction in HPCs, and the calcium influx assay.

Results: OCT directly upregulated the transcription of Dcx in HPCs via activation of peroxisome proliferator-activated receptor α (PPARα), a lipid-lowering transcription factor. We observed that, HPCs of Ppara-null mice displayed significant impairment in DCX expression and neuronal differentiation as compared to that of wild-type mice. Interestingly, treatment with OCT stimulated the differentiation process of HPCs in wild-type, but not Ppara-null mice. Reconstruction of PPARα in mouse Ppara-null HPCs restored the expression of DCX, which was further stimulated with OCT treatment. In contrast, a dominant-negative mutant of PPARα significantly attenuated the stimulatory effect of OCT on DCX expression and suppressed neuronal differentiation of human neural progenitor cells. Furthermore, RNA microarray, STRING, chromatin immunoprecipitation, site-directed mutagenesis, and promoter reporter assay have identified DCX as a new target of PPARα.

Conclusion: These results indicate that OCT, a sleep supplement, directly controls the expression of DCX and suggest that OCT may be repurposed for stimulating the hippocampal neurogenesis.

Keywords: Doublecortin; PPARα; hippocampal progenitor cells; oleamide.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Differentiation / drug effects
  • Doublecortin Domain Proteins*
  • Food Additives / administration & dosage*
  • Gene Expression Regulation
  • Hippocampus / metabolism
  • Humans
  • Mice
  • Mice, Knockout
  • Oleic Acids / administration & dosage*
  • PPAR alpha / metabolism*
  • Promoter Regions, Genetic*
  • Sleep / drug effects
  • Sleep Aids, Pharmaceutical / pharmacology*
  • Transcription Factors / genetics
  • Up-Regulation*


  • Doublecortin Domain Proteins
  • Food Additives
  • Oleic Acids
  • PPAR alpha
  • Sleep Aids, Pharmaceutical
  • Transcription Factors
  • oleylamide