Pharmacological Activation of the Nuclear Receptor REV-ERB Reverses Cognitive Deficits and Reduces Amyloid-β Burden in a Mouse Model of Alzheimer's Disease

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2019 Apr 12

PMID 30973894

Citations 13

Authors

Deborah A Roby

Fernanda Ruiz

Bailey A Kermath

Jaymie R Voorhees

Michael Niehoff

Jinsong Zhang

John E Morley

Erik S Musiek

Susan A Farr

Thomas P Burris

Affiliations

Soon will be listed here.

Abstract

Alzheimer's disease currently lacks treatment options that effectively reverse the biological/anatomical pathology and cognitive deficits associated with the disease. Loss of function of the nuclear receptor REV-ERB is associated with reduced cognitive function in mouse models. The effect of enhanced REV-ERB activity on cognitive function has not been examined. In this study, we tested the hypothesis that enhanced REV-ERB function may enhance cognitive function in a model of Alzheimer's disease. We utilized the REV-ERB agonist SR9009 to pharmacologically activate the activity of REV-ERB in the SAMP8 mouse model of Alzheimer's disease. SR9009 reversed cognitive dysfunction of an aged SAMP8 mouse in several behavioral assays including novel object recognition, T-maze foot shock avoidance, and lever press operant conditioning task assessments. SR9009 treatment reduced amyloid-β 1-40 and 1-42 levels in the cortex, which is consistent with improved cognitive function. Furthermore, SR9009 treatment led to increased hippocampal PSD-95, cortical synaptophysin expression and the number of synapses suggesting improvement in synaptic function. We conclude that REV-ERB is a potential target for treatment of Alzheimer's disease.

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