Small molecule modulator of sigma 2 receptor is neuroprotective and reduces cognitive deficits and neuroinflammation in experimental models of Alzheimer's disease
| Autor: | Jessica Z. Chan, Jonathan T. Pierce, Pooneh Memar Ardestani, Luisa L. Scott, Stephen F. Martin, Bitna Yi, Sangeetha Iyer, Ashley Crisp, Gabriella Zuniga, Andrew K. Evans, James J. Sahn, Mehrdad Shamloo |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Genetically modified mouse Amyloid Sigma-2 receptor Mice Transgenic Biology Ligands Biochemistry Neuroprotection Article Mice 03 medical and health sciences Cellular and Molecular Neuroscience Alzheimer Disease Cell Line Tumor Progesterone receptor medicine Animals Humans Receptors sigma PGRMC1 Neuroinflammation Inflammation Dose-Response Relationship Drug Neurodegeneration medicine.disease Mice Inbred C57BL Disease Models Animal Neuroprotective Agents 030104 developmental biology Inflammation Mediators Cognition Disorders Neuroscience Protein Binding |
| Zdroj: | Journal of Neurochemistry. 140:561-575 |
| ISSN: | 0022-3042 |
| DOI: | 10.1111/jnc.13917 |
| Popis: | Accumulating evidence suggests that modulating the sigma 2 receptor (Sig2R) can provide beneficial effects for neurodegenerative diseases. Herein, we report the identification of a novel class of Sig2R binding ligands and their cellular and in vivo activity in experimental models of Alzheimer’s disease (AD). We report that SAS-0132 and DKR-1051, selective ligands of Sig2R, modulate intracellular Ca2+ levels in human SK-N-SH neuroblastoma cells. The Sig2R antagonists SAS-0132 and JVW-1009 are neuroprotective in a C. elegans model of amyloid precursor protein-mediated neurodegeneration. Since this neuroprotective effect is replicated by genetic knockdown and knockout of vem-1, the ortholog of progesterone receptor membrane component-1 (PGRMC1), it indicates that Sig2R ligands modulate a PGRMC1-related pathway. Last, we demonstrate that SAS-0132 improves cognitive performance both in the Thy-1 hAPPLond/Swe+ transgenic mouse model of AD and in healthy wild-type mice. These results demonstrate that Sig2R is a promising therapeutic target for neurocognitive disorders including AD. |
| Databáze: | OpenAIRE |
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