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

Roby DA, Ruiz F, Kermath BA, Voorhees JR, Niehoff M, Zhang J, Morley JE, Musiek ES, Farr SA, Burris TP
PLoS One. 2019 14 (4): e0215004

PMID: 30973894 · PMCID: PMC6459530 · DOI:10.1371/journal.pone.0215004

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.

MeSH Terms (13)

Alzheimer Disease Amyloid beta-Peptides Animals Cognitive Dysfunction Disease Models, Animal Disks Large Homolog 4 Protein Hippocampus Male Mice Nuclear Receptor Subfamily 1, Group D, Member 1 Peptide Fragments Pyrrolidines Thiophenes

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