Pharmacological activation of the nuclear receptor REV-ERB reverses cognitive deficits and reduces amyloid-β burden in a mouse model of Alzheimer's disease
| Autor: | Thomas P. Burris, John E. Morley, Fernanda Ruiz, Jaymie R. Voorhees, Deborah A Roby, Erik S. Musiek, Bailey A. Kermath, Susan A. Farr, Jinsong Zhang, Michael L. Niehoff |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Agonist Male Pyrrolidines medicine.drug_class Science Hippocampus Disease Thiophenes Hippocampal formation 03 medical and health sciences Mice 0302 clinical medicine Alzheimer Disease medicine Animals Cognitive Dysfunction skin and connective tissue diseases Loss function Multidisciplinary Amyloid beta-Peptides biology business.industry Cognition Peptide Fragments Cortex (botany) body regions Disease Models Animal 030104 developmental biology Nuclear Receptor Subfamily 1 Group D Member 1 Synaptophysin biology.protein Medicine business Neuroscience Disks Large Homolog 4 Protein 030217 neurology & neurosurgery |
| Zdroj: | PLoS ONE, Vol 14, Iss 4, p e0215004 (2019) |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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