RbAp48 Protein is a critical component of GPR158/OCN signaling and Ameliorates Age-Related Memory Loss

Deciphering precisely the molecular mechanisms of Age-Related Memory Loss is of great importance to create the appropriate therapeutic interventions. We have previously shown that the histone binding protein RbAp48/Rbbp4 is a molecular determinant of Aged Related Memory Loss. In an effort to explore how this protein regulates the genomic landscape in the hippocampal circuit, we find that RbAp48 controls the expression of BDNF and GPR158 proteins, both critical components of Osteocalcin’s (OCN) signaling in the mouse hippocampus. We show that inhibition of RbAp48 in the hippocampal formation renders OCN’s beneficial functions in cognition ineffective and causes deficits in discrimination memory. In turn, disruption of OCN/GPR158 signaling leads to the downregulation of RbAp48 protein mimicking the discrimination memory deficits observed in the aged hippocampus. We also show that activation of OCN/GPR158 pathway increases the expression of RbAp48 in the aged dentate gyrus and rescues Aged Related Memory Loss.