Pharmacological activation of the nuclear receptor REV-ERB reverses cognitive deficits and reduces amyloid-β burden in a mouse model of Alzheimer's disease.

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.

• 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
• Journal: PloS one (PLoS One) Vol. 14 Issue 4 Pg. e0215004 ( 2019) ISSN: 1932-6203 [Electronic] United States
• PMID: 30973894 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Amyloid beta-Peptides
• Disks Large Homolog 4 Protein
• Dlg4 protein, mouse
• Nuclear Receptor Subfamily 1, Group D, Member 1
• Peptide Fragments
• Pyrrolidines
• SR9009
• Thiophenes
• amyloid beta-protein (1-40)
• amyloid beta-protein (1-42)

Topics

• Alzheimer Disease (drug therapy, metabolism, pathology)
• Amyloid beta-Peptides (metabolism)
• Animals
• Cognitive Dysfunction (drug therapy, metabolism, pathology)
• Disease Models, Animal
• Disks Large Homolog 4 Protein (metabolism)
• Hippocampus (metabolism, pathology)
• Male
• Mice
• Nuclear Receptor Subfamily 1, Group D, Member 1 (metabolism)
• Peptide Fragments (metabolism)
• Pyrrolidines (pharmacology)
• Thiophenes (pharmacology)