Cholesterol loss in old hippocampus triggers HDAC2 mediated repression of BDNF

DE LA CRUZ-THEA, BENJAMIN; HARMAN, MARÍA F.; MAURICIO G MARTÍN

Congreso; Encuentro de la Sociedad Argentina de Neurociencias 2022; 2022

Aging is associated to epigenetic alterations that result in decreased expression ofmemory genes. Among all these alterations, impaired histone acetylation mediated byHistone deacetylase 2 (HDAC2) has been considered one of the main determinants ofmemory loss during aging. We have focused our studies in the factors leading toHDAC2 repression of memory genes in old neurons. In this study, we show that agingtriggers HDAC2 accumulation on the regulatory regions of the Bdnf gene, a key factorinvolved in synaptic plasticity. We found that the transcriptional repressorChromodomain Y like protein (CDYL), which directly interacts with HDAC2 inhippocampal extracts, accumulates in the nuclei of old neurons. Taking into accountthat CDYL degradation is triggered by synaptic activity, our data indicate that CDYLaccumulation could be explained by impaired activity of NMDA receptors as aconsequence of reduced cholesterol levels in old neurons. We also found a decay ofSphingosine kinase 2 (Sphk2) in old hippocampus, a protein which is able to repressHDAC2 activity through the synthesis of Sphingosine-1-phosphate. Thus, Sphk2reduction implicates another level of repression in addition to HDAC2 recruitment toBdnf promoters in old neurons.