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 Ca 2+ 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 ( PGRMC 1), these results suggest that Sig2R ligands modulate a PGRMC 1‐related pathway. Last, we demonstrate that SAS ‐0132 improves cognitive performance both in the Thy‐1 hAPP L ond/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 .