Date Published: April 11, 2019
Publisher: Public Library of Science
Author(s): 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, Masuo Ohno.
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.
REV-ERBs (REV-ERBα and β) are nuclear receptors that function as a ligand-dependent suppressors of gene transcription and are a critical components of the mammalian circadian clock [1–5]. Additionally, the REV-ERBs play important roles in physiological pathways including metabolism and inflammation [6–8]. Although their role in circadian behavior has been known for some time, more recent studies suggest that they also play an important role in learning and memory. Rev-erbα null mice display impaired short-term, long-term, and contextual memory and increased hippocampal neurogenesis [9–11]. REV-ERB recruits corepressors and class 1 histone deacetylases (HDACs) to target gene promoters and class 1 HDACs have also been implicated in learning and memory . A number of synthetic agonists that activate REV-ERBs’ transcriptional suppressor activity have been designed to assess the effects of modulating REV-ERB activity in vivo [13,14], but no studies examining their effects on cognitive function have been described.
Since genetic Rev-erbα loss of function results in reduced cognitive function, we hypothesized that increased REV-ERB activity may increase cognitive function in diseases where cognitive function is impaired. We used the SAMP8 mouse model of premature aging and AD to assess the ability of a REV-ERB agonist to alter cognitive function. We treated one set of “old” 12-month-old SAMP8 mice with SR9009 (O-SR9009; 14 days, 100 mg/kg q.d.), one set of 12-month-old SAMP8 mice with vehicle (O-V), and one set of “young” 4-month-old SAMP8 mice with vehicle (Y-V) and subjected them to three different behavioral tasks: novel object recognition (NOR), T-maze foot shock avoidance, and lever press operant conditioning. In the NOR test, reduced time spent exploring a novel object (reduced discrimination index) is associated with reduced cognitive function (reduction in the natural tendency of mice to investigate novel aspects of their environment). The hippocampus is involved in the 24-hour consolidation period between the introduction and recollection of novel objects , and this hippocampal-dependent memory assay is low stress and exposes cognitive impairments similar to those found in AD.
We have demonstrated that gain of REV-ERB function through pharmacological activation with SR9009 reversed cognitive defects in an AD mouse model. Mechanistically, we noted that SR9009 led to decreased Aβ levels in the brain as well as increased expression of markers of synaptic health and improved axoskeletal structure. These data clearly suggest that targeting of REV-ERB may be a method to effectively treat AD as well as other cognitive disorders.