Small molecule modulator of sigma 2 receptor is neuroprotective and reduces cognitive deficits and neuroinflammation in experimental models of Alzheimer's disease

J Neurochem. 2017 Feb;140(4):561-575. doi: 10.1111/jnc.13917.


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.

Keywords: Alzheimer's disease; Sig2R/PGRMC1; intracellular calcium; learning and memory; neuroprotection.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / prevention & control
  • Animals
  • Cell Line, Tumor
  • Cognition Disorders / genetics
  • Cognition Disorders / metabolism*
  • Cognition Disorders / prevention & control
  • Disease Models, Animal*
  • Dose-Response Relationship, Drug
  • Humans
  • Inflammation / drug therapy
  • Inflammation / genetics
  • Inflammation / metabolism
  • Inflammation Mediators / antagonists & inhibitors
  • Inflammation Mediators / metabolism*
  • Ligands
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / metabolism*
  • Neuroprotective Agents / therapeutic use
  • Protein Binding / physiology
  • Receptors, sigma / antagonists & inhibitors
  • Receptors, sigma / genetics
  • Receptors, sigma / metabolism*


  • Inflammation Mediators
  • Ligands
  • Neuroprotective Agents
  • Receptors, sigma
  • sigma-2 receptor