HDAC2 mediated repression of BDNF in old hippocampus triggered by cholesterol loss

DE LA CRUZ-THEA, BENJAMIN; MAURICIO G MARTÍN

Congreso; Reunión SAIB 2022; 2022

Aging is associated to epigenetic alterations which lead to diminished expression ofmemory-related genes. One of the main alterations in the aging brain is cholesterolloss. This lipid is capable of interacting both with sphingolipids and proteins and thusplay a key role in Membrane Lipid Rafts formation (MLR), key structures for properfunction of some receptors such as the NMDAR. The cholesterol loss during agingreduces MLR formation and impairs proper NMDAR activation and synaptic-activitydependent transcription of memory-genes. Contributing to this process, a decrease inhistone residues acetylation due to Histone Deacetylase 2 (HDAC2) accumulation hasbeen observed. This particular event is determinant for memory loss during aging. Inthis work, we found that aging triggers the accumulation of HDAC2 in promoters II andVI of the BDNF gene, a key transcription factor for synaptic plasticity, learning andmemory formation. We found that the transcriptional co-repressor Chromodomain Ylike protein (CDYL), which interacts with HDAC2 in hippocampal extracts, isaccumulated in the nucleus of old neurons. In addition, the co-accumulation of CDYLand HDAC2 was observed in neurons of transgenic Thy-1(GFP) mice brain slices andafter cholesterol oxidase treatment in 14-DIV rat hippocampal neurons. Taking intoaccount that has been reported that CDYL degradation is triggered by synaptic activity,and we observe a decrease in CDYL mean fluorescence intensity after NDMAstimulation, we propose that CDYL accumulation can occur as a consequence ofimpaired NMDA receptor activation due to reduced MLR formation. The findings ofthis work contribute to the understanding of the epigenetic mechanisms underlyingsynaptic impairment during aging.