Small molecule modulator of sigma 2 receptor is neuroprotective and reduces cognitive deficits and neuroinflammation in experimental models of Alzheimer's disease.
Small molecule modulator of sigma 2 receptor is neuroprotective and reduces cognitive deficits and neuroinflammation in experimental models of Alzheimer's disease.
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DOI：
10.1111/jnc.13917
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发表时间：
2017-02
影响因子：
4.7
通讯作者：
Shamloo M
中科院分区：
文献类型：
--
作者：
Yi B;Sahn JJ;Ardestani PM;Evans AK;Scott LL;Chan JZ;Iyer S;Crisp A;Zuniga G;Pierce JT;Martin SF;Shamloo M
越来越多的证据表明，调节sigma 2受体（Sig 2 R）可以为神经退行性疾病提供有益的效果。在此，我们报告了一类新型Sig 2 R结合配体的鉴定及其在阿尔茨海默病（AD）实验模型中的细胞和体内活性。我们报道了Sig 2 R的选择性配体SAS-0132和DKR-1051调节人SK-N-SH神经母细胞瘤细胞内Ca ~（2+）水平。Sig 2 R拮抗剂SAS-0132和JVW-1009在C.淀粉样前体蛋白介导的神经变性的elegans模型。由于这种神经保护作用是通过基因敲除和vem-1（孕酮受体膜组分-1（PGRMC 1）的直系同源物）敲除复制的，因此表明Sig 2 R配体调节PGRMC 1相关途径。最后，我们证明了SAS-0132改善了AD的Thy-1 hAPPLond/Swe+转基因小鼠模型和健康野生型小鼠的认知表现。这些结果表明Sig 2 R是包括AD在内的神经认知障碍的有希望的治疗靶标。
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 binding 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 antagonists 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), it indicates 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.