The role of folate receptor α in the partial rejuvenation of dentate gyrus cells. Improvement of cognitive function in elderly mice

Abstract In this work, we have studied the effect of small compounds in the partial rejuvenation of dentate gyrus cells by measuring the improvement of cognitive functions in elderly mice. Aging has been related to a change in DNA methylation and some one-carbon metabolites linked to that methylation process, like vitamin B12, folate or methionine have been involved in cognitive performance during aging. However, their role in this process and the possible mechanisms behind its cognitive effects are still unclear. Through direct infusion of these molecules in the dentate gyrus we have tested their effects on cognition in elderly mice. Only positive results were found for folate. A partial rejuvenation of dentate gyrus cells related to an increase in neuroplasticity by reorganizing extracellular matrix structures and rising the expression of juvenile genes like GluN2B was found. Since folate is involved in several cellular pathways in addition to DNA methylation, we have focused in its interaction with its folate receptor alpha (FRα), a protein that is present at the cell nucleus, acting as transcription factor. We have found that most of folate effects on brain would be mediated by the activation of FRα. In addition, we propose that the mechanism for cell rejuvenation by folate, or other FRα binding molecules, may involve the expression of proteins, like SOX2, a Yamanaka factor present in young neurons. Thus, the use of molecules that activate the FRα pathway could constitute an interesting strategy to be considered for the study of brain rejuvenation.