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

Article type: Research Article

Authors: Roy, Avik^{a; *} | Kundu, Madhuchhanda^a | Chakrabarti, Sudipta^a | Patel, Dhruv R.^a | Pahan, Kalipada^{a; b; *}

Affiliations: [a] Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA | [b] Division of Research and Development, Jesse Brown Veterans Affairs Medical Center, Chicago, IL, USA

Correspondence: [*] Correspondence to: Kalipada Pahan, PhD, Department of Neurological Sciences, Rush University Medical Center, 1735 West Harrison St, Suite 320, Chicago, IL 60612, USA. Tel.: +1 312 563 3592; Fax: +1 312 563 3571; E-mail: [email protected] Avik Roy, PhD, Department of Neurological Sciences, Rush University Medical Center, 1735 West Harrison St, Suite 340, Chicago, IL 60612, USA. Tel.: +1 312 942 8274; E-mail: [email protected].

Abstract: 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, hippocampal progenitor cells, oleamide, PPARα

DOI: 10.3233/JAD-215124

Journal: Journal of Alzheimer's Disease, vol. 84, no. 4, pp. 1747-1762, 2021