title: Small molecule modulator of sigma 2 receptor is neuroprotective and reduces cognitive deficits and neuroinflammation in experimental models of Alzheimer's disease.
abstract: 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.
authors.affiliation: Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, California, USA.
authors.forename: Bitna
authors.initials: B
authors.lastname: Yi
authors.affiliation: Department of Chemistry, The University of Texas at Austin, Austin, Texas, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Sahn
authors.affiliation: Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, California, USA.
authors.forename: Pooneh Memar
authors.initials: PM
authors.lastname: Ardestani
authors.affiliation: Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, California, USA.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Evans
authors.affiliation: Waggoner Center for Alcohol and Addiction Research, Institute of Neuroscience, Center for Learning and Memory, Center for Brain, Behavior and Evolution and Department of Neuroscience, The University of Texas at Austin, Austin, Texas, USA.
authors.forename: Luisa L
authors.initials: LL
authors.lastname: Scott
authors.affiliation: Department of Chemistry, The University of Texas at Austin, Austin, Texas, USA.
authors.forename: Jessica Z
authors.initials: JZ
authors.lastname: Chan
authors.affiliation: Waggoner Center for Alcohol and Addiction Research, Institute of Neuroscience, Center for Learning and Memory, Center for Brain, Behavior and Evolution and Department of Neuroscience, The University of Texas at Austin, Austin, Texas, USA.
authors.forename: Sangeetha
authors.initials: S
authors.lastname: Iyer
authors.affiliation: Waggoner Center for Alcohol and Addiction Research, Institute of Neuroscience, Center for Learning and Memory, Center for Brain, Behavior and Evolution and Department of Neuroscience, The University of Texas at Austin, Austin, Texas, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Crisp
authors.affiliation: Waggoner Center for Alcohol and Addiction Research, Institute of Neuroscience, Center for Learning and Memory, Center for Brain, Behavior and Evolution and Department of Neuroscience, The University of Texas at Austin, Austin, Texas, USA.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Zuniga
authors.affiliation: Waggoner Center for Alcohol and Addiction Research, Institute of Neuroscience, Center for Learning and Memory, Center for Brain, Behavior and Evolution and Department of Neuroscience, The University of Texas at Austin, Austin, Texas, USA.
authors.forename: Jonathan T
authors.initials: JT
authors.lastname: Pierce
authors.affiliation: Department of Chemistry, The University of Texas at Austin, Austin, Texas, USA.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Martin
authors.affiliation: Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, California, USA.
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Shamloo
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D000818:Animals; D045744:Cell Line, Tumor; D003072:Cognition Disorders / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D011485:Protein Binding / Q000502:physiology; D017480:Receptors, sigma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D018836:Inflammation Mediators; D008024:Ligands; D018696:Neuroprotective Agents; D017480:Receptors, sigma; C106107:sigma-2 receptor
keywords: Alzheimer's disease; Sig2R/PGRMC1; intracellular calcium; learning and memory; neuroprotection