期刊
JOURNAL OF NEUROCHEMISTRY
卷 140, 期 4, 页码 561-575出版社
WILEY
DOI: 10.1111/jnc.13917
关键词
Alzheimer's disease; intracellular calcium; learning and memory; neuroprotection; Sig2R/PGRMC1
资金
- NIH Office of Research Infrastructure Programs [P40 OD010440]
- National Institutes of Health [GM 24539, 1R01AG041135, NS069375]
- Robert A. Welch Foundation [F-0652]
- Alzheimer's Association
- Lumind Research Foundation
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 hAPP(Lond/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.
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