Small molecule modulator of sigma 2 receptor is neuroprotective and reduces cognitive deficits and neuroinflammation in experimental models of Alzheimer's disease
详细信息 查看全文
- 作者：Bitna Yi ; James J. Sahn ; Pooneh Memar Ardestani ; Andrew K. Evans ; Luisa L. Scott ; Jessica Z. Chan ; Sangeetha Iyer ; Ashley Crisp ; Gabriella Zuniga ; Jonathan T. Pierce ; Stephen F. Martin and Mehrdad Shamloo
- 刊名：Journal of Neurochemistry
- 出版年：2017
- 出版时间：February 2017
- 年：2017
- 卷：140
- 期：4
- 页码：561-575
- 全文大小：1245K
- ISSN：1471-4159
文摘
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 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 ligands 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), these results suggest 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.