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.
Highlights
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 [1,2,3,4,5]
We used the senescence accelerated mouse prone 8 (SAMP8) mouse model of premature aging and Alzheimer’s disease (AD) to assess the ability of a REV-ERB agonist to alter cognitive function
The old mice receiving vehicle (O-V) SAMP8 mice displayed decreased cognitive function in all the tests relative to the Y-V SAMP8 mice, and in nearly every case, SR9009 treatment resulted in significantly improved cognitive function in the O-SR9009 mice relative to the O-V mice (Fig 1)
Summary
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 [1,2,3,4,5]. The REV-ERBs play important roles in physiological pathways including metabolism and inflammation [6,7,8]. Their role in circadian behavior has been known for some time, more recent studies suggest that they play an important role in learning and memory.
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