Activation of PPARα Stimulates Hippocampal Neurogenesis

Little is known about the molecular mechanism of hippocampal neurogenesis. Here, we delineate an important role of PPARα, a lipid-lowering transcription factor, in hippocampal neurogenesis. Interestingly, progenitor cells derived from hippocampus of Ppara-null mice displayed significant impairment in neuronal differentiation as compared to that of wild-type mice. BrdU incorporation assay into PparaΔHip (hippocampus-specific knockout), PparaΔHep (liver-specific knockout) and PparaΔAst (astrocyte-specific knockout) mice revealed that the absence of PPARα in neurons, but neither astroglia nor liver, impaired hippocampal neurogenesis. Detailed genomic analyses including RNA array, STRING, chromatin immunoprecipitation, site-directed mutagenesis, and promoter reporter assay have identified prototype neurogenesis marker DCX as a new target of PPARα. Furthermore, analysis of human postmortem brain of no-cognitive impairment (NCI) and Alzheimer (AD) patients as well as FAD5X mice indicated that PPARα directly regulated the expression of DCX in dentate gyrus (DG). Interestingly, oral administration of 9-octadecenamide (OCT), an endogenous ligand of PPARα from hippocampus and a sleep-inducing supplement in humans, increased the level of PPARα and DCX in the DG and improved spatial learning and memory in FAD5X, but not FAD5X/Ppara-null, mice. These results indicate a new role of PPARα in controlling hippocampal neurogenesis and suggest that OCT may be repurposed for preserving hippocampal neurogenesis and improving memory and learning in AD and dementia.