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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 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 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. image
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S2R modulators tested by several independent groups are neuroprotective, synaptoprotective, block toxic amyloid-β oligomers from binding to neuronal synapses, and restore neuronal functioning and cognitive deficits across various preclinical models.
“S2R modulators tested by several independent groups have been shown to be neuroprotective, be synaptoprotective, block toxic amyloid-β oligomers from binding to neuronal synapses, and restore neuronal functioning and cognitive deficits across various preclinical models, from neurons in culture to in vivo Alzheimer’s disease models from C. elegans to rodents [141].”
From Sigma-2 Receptors—From Basic Biology to Therapeutic Target: A Focus on Age-Related Degenerative Diseases (2023) · cites this paper as [141]
In vivo, the S2R modulator SAS-0132 produces neuroprotective, cognitive enhancing, and anti-inflammatory effects in a rodent model of Alzheimer's disease.
“In vivo, the S2R modulator SAS-0132 has been shown to produce neuroprotective, cognitive enhancing, and anti-inflammatory effects in a rodent model of Alzheimer’s disease [141].”
From Sigma-2 Receptors—From Basic Biology to Therapeutic Target: A Focus on Age-Related Degenerative Diseases (2023) · cites this paper as [141]
Sigma-2 receptor ligands prevent neurodegeneration in a worm model expressing human amyloid precursor protein.
“Yi et al.and Mondal et al.similarly found that Sigma-2 receptor ligands prevent neurodegeneration in a worm model expressing human amyloid precursor protein [44, 77].”
From Transmembrane protein 97 is a potential synaptic amyloid beta receptor in human Alzheimer’s disease (2024) · cites this paper as [77]
TMEM97 is believed to be a key player of calcium regulation.
“TMEM97, initially known as MAC30 [47], is overexpressed in some cancers and it is believed to be a key player of cholesterol homeostasis [78] and calcium regulation [8, 74, 77].”
From Transmembrane protein 97 is a potential synaptic amyloid beta receptor in human Alzheimer’s disease (2024) · cites this paper as [77]
In an animal model with Alzheimer's-like plaque deposition, TMEM97 (Sigma-2) modulators improved cognitive deficits.
“In an animal model with Alzheimer’s-like plaque deposition, TMEM97 (Sigma-2) modulators improved cognitive deficits [27, 77].”
From Transmembrane protein 97 is a potential synaptic amyloid beta receptor in human Alzheimer’s disease (2024) · cites this paper as [77]
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Metadata
- Authors
- Yi, B., Sahn, J. J., Ardestani, P. M., Evans, A. K., Scott, L. L., Chan, J. Z., Iyer, S., Crisp, A., Zuniga, G., Pierce, J. T., Martin, S. F., & Shamloo, M.
- Affiliations
- Department of Neurosurgery Stanford University School of Medicine Palo Alto California USA
- Department of Chemistry The University of Texas at Austin Austin Texas USA
- 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
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2017-02
- Volume
- 140
- Issue
- 4
- Pages
- 561-575
- ISSN
- 0022-3042
- 1471-4159
- PMC
- PMC5312682
- Cited by
- 116
- References
- 10
- Language
- en
- Funders
- National Institutes of Health (GM 24539, 1R01AG041135, NS069375)
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