Sigma 1 receptor as therapeutic target for Alzheimers disease treatment

摘要 这项赠款申请的广泛、长期的目标是了解 S1R激动剂对阿尔茨海默病的神经保护作用。最近的临床和 临床前数据表明，S1R的激活可能促进神经元的弹性并导致突触保护 以及AD环境中的神经保护作用。S1R基因突变与运动神经退行性变有关 神经元和SIGMA1R基因的多态与晚发性AD的发病风险有关。 这些联系促使正在进行和计划中的S1R激动剂在AD中的2期和3期临床试验 病人。尽管S1R对神经生理学和药物靶点很重要，但它的生物学功能是 在临床前和临床研究中，对S1R激动剂的了解和作用机制还不是很好 已经成立了。这项拨款提案的主要目的是评估突触保护的假说 S1R激动剂对阿尔茨海默病的神经保护作用部分是通过其重塑 线粒体相关膜(MAM)和其他富含胆固醇的内质网(ER) 微域。这一假设是基于我们最近发现的S1R关联的生物学重要性 胆固醇及其在形成MAM和内质网微域中的作用。为了检验这一假设，特别是我们 将(1)研究S1R序列中的胆固醇结合位点对AD患者体内突触挽救的重要性 (2)分析S1R激活对阿尔茨海默病(AD)大鼠肺泡巨噬细胞脂质成分变化的影响；(3)测定 星形胶质细胞ApoE释放增加在S1R激动剂神经保护作用中的作用 S1R激活引起的神经元钙信号变化的重要性。所取得的成果 拟议的研究将提供有关S1R激动剂在模型中的作用机制的基本信息 AD，促进对正在进行的S1R激动剂的AD临床试验的解释，并有可能导致开发 用于AD治疗的下一代S1R靶向治疗剂。

ABSTRACT The broad, long-term objective of this grant application is to understand the mechanisms involved in neuroprotective action of sigma 1 receptor (S1R) agonists Alzheimer’s disease (AD). Recent clinical and preclinical data suggest that activation of S1R may promote neuronal resilience and result in synaptoprotective and neuroprotective effects within an AD context. Mutations in S1R are linked with degeneration of motor neurons and polymorphisms in SIGMA1R gene have been linked with the risk of developing late onset AD. These links have prompted on-going and planned phase 2 and phase 3 clinical trials of S1R agonists in AD patients. Despite its importance for neuronal physiology and as a drug target, the biological function of S1R is poorly understood and mechanism of action of S1R agonists in preclinical and clinical studies is not well established. The main aim of this grant proposal is to evaluate the hypothesis that synaptoprotective and neuroprotective effects of S1R agonists in AD are mediated in part by their remodeling of mitochondria-associated membranes (MAMs) and other endoplasmic reticulum (ER) cholesterol-rich microdomains. This hypothesis is based on our recent discovery of biological importance of S1R association with cholesterol and its role in forming MAMs and ER microdomains. To test this hypothesis, specifically we will (1) investigate an importance of cholesterol-binding site in S1R sequence for in vivo synaptic rescue in AD mice; (2) analyze effects of S1R activation on changes of lipid composition of MAMs in AD; (3) determine a role of enhanced ApoE release from astrocytes for neuroprotective effects of S1R agonists; (4) establish an importance of neuronal calcium signaling changes resulting from S1R activation. Results obtained in the proposed studies will provide essential information regarding mechanism of action of S1R agonists in models of AD, facilitate interpretation of on-going AD clinical trials of S1R agonists, and potentially lead to development of the next generation of S1R-targeting therapeutic agents for AD treatment.