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

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. Sigma2R has emerged as a binding site for the oligomeric amyloid beta and modulator of CNS pathology. Here, we report that pharmacological and genetic modulation of Sigma2R is neuroprotective, cognitive enhancing, and antiinflammatory in animal models of Alzheimer's disease by potentially regulating cellular calcium homeostasis. Further elucidation of other receptors and signaling cascades associated with Sigma2R is required and underway.