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Cell Rep. 2018 Oct 23;25(4):959-973.e6. doi: 10.1016/j.celrep.2018.09.077.

RbAp48 Protein Is a Critical Component of GPR158/OCN Signaling and Ameliorates Age-Related Memory Loss.

Author information

1
Department of Neuroscience, Columbia University, New York, NY 10032, USA; Howard Hughes Medical Institute, Columbia University, New York, NY 10032, USA; New York State Psychiatric Institute, New York, NY 10032, USA; Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10032, USA.
2
Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece; Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
3
Department of Psychiatry, Columbia University, New York, NY 10032, USA.
4
Department of Psychiatry, Columbia University, New York, NY 10032, USA; Division of Systems Neuroscience, New York State Psychiatric Institute (NYSPI)/Research Foundation for Mental Hygiene, Inc. (RFMH), New York, NY 10032, USA.
5
New York State Psychiatric Institute, New York, NY 10032, USA; Department of Psychiatry, Columbia University, New York, NY 10032, USA.
6
Department of Neuroscience, Columbia University, New York, NY 10032, USA; New York State Psychiatric Institute, New York, NY 10032, USA; Kavli Institute for Brain Science, Columbia University, New York, NY 10032, USA; Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10032, USA. Electronic address: erk5@cumc.columbia.edu.

Abstract

Precisely deciphering the molecular mechanisms of age-related memory loss is crucial to create appropriate therapeutic interventions. We have previously shown that the histone-binding protein RbAp48/Rbbp4 is a molecular determinant of Age-Related Memory Loss. By exploring how this protein regulates the genomic landscape of the hippocampal circuit, we find that RbAp48 controls the expression of BDNF and GPR158 proteins, both critical components of osteocalcin (OCN) signaling in the mouse hippocampus. We show that inhibition of RbAp48 in the hippocampal formation inhibits OCN's beneficial functions in cognition 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 the OCN/GPR158 pathway increases the expression of RbAp48 in the aged dentate gyrus and rescues age-related memory loss.

KEYWORDS:

RbAp48; aging; hippocampus; memory; osteocalcin

PMID:
30355501
DOI:
10.1016/j.celrep.2018.09.077
[Indexed for MEDLINE]
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