Early intervention with an estrogen receptor β-selective phytoestrogenic formulation prolongs survival, improves spatial recognition memory, and slows progression of amyloid pathology in a female mouse model of Alzheimer's disease.
Early intervention with an estrogen receptor β-selective phytoestrogenic formulation prolongs survival, improves spatial recognition memory, and slows progression of amyloid pathology in a female mouse model of Alzheimer's disease.
复制标题
DOI：
10.3233/jad-122341
复制
发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Brinton RD
中科院分区：
文献类型：
--
作者：
Zhao L;Mao Z;Chen S;Schneider LS;Brinton RD
我们最近的研究已经产生了一种新的植物雌激素制剂，称为植物β-SerM制剂，它对雌激素受体亚型β(ERβ)的结合选择性是ERα的83倍。早期的研究表明，植物-β-SerM制剂具有神经保护作用，并促进大脑中的雌激素机制，而外周缺乏女性化活性。在人类更年期小鼠模型中的进一步研究表明，长期暴露于临床相关剂量的植物-β-SerM制剂可以预防/缓解与更年期相关的更年期症状。这项研究在早期干预范例中评估了植物-β-SerM配方在调节与阿尔茨海默病(AD)相关的早期生理和神经变化方面的有效性，该模型是在一个雌性三重转基因AD小鼠模型中进行的。结果表明，在AD病理出现之前开始，9个月的饮食补充与植物-β-SerM配方促进了身体健康，延长了存活期，改善了空间识别记忆，并减少了淀粉样蛋白β在治疗后的AD小鼠大脑中的沉积和斑块形成。相比之下，饮食补充一种商业大豆提取物制剂对认知指标没有影响，尽管它似乎对淀粉样蛋白病理有积极影响。与行为和组织学结果总体一致的是，基因表达谱分析的结果提供了与两种饮食治疗相关的潜在分子机制的见解。特别是，数据表明，ERβ和糖原合成酶激酶3信号通路之间可能存在串扰，这可能在ERβ介导的抗AD神经保护中发挥作用。综上所述，这些结果支持植物-β-SerM配方在预防和/或早期干预AD方面的治疗潜力，并值得在人体研究中进行进一步的研究。
Our recent developments have yielded a novel phytoestrogenic formulation, referred to as the phyto-β-SERM formulation, which exhibits an 83-fold binding selectivity for the estrogen receptor subtype β (ERβ) over ERα. Earlier studies indicate that the phyto-β-SERM formulation is neuroprotective and promotes estrogenic mechanisms in the brain while devoid of feminizing activity in the periphery. Further investigation in a mouse model of human menopause indicates that chronic exposure to the phyto-β-SERM formulation at a clinically relevant dosage prevents/alleviates menopause-related climacteric symptoms. This study assessed the efficacy, in an early intervention paradigm, of the phyto-β-SERM formulation in the regulation of early stages of physical and neurological changes associated with Alzheimer’s disease (AD) in a female triple transgenic mouse model of AD. Results demonstrated that, when initiated prior to the appearance of AD pathology, a 9-month dietary supplementation with the phyto-β-SERM formulation promoted physical health, prolonged survival, improved spatial recognition memory, and attenuated amyloid-β deposition and plaque formation in the brains of treated AD mice. In comparison, dietary supplementation of a commercial soy extract preparation showed no effect on cognitive measures, although it appeared to have a positive impact on amyloid pathology. In overall agreement with the behavioral and histological outcomes, results from a gene expression profiling analysis offered insights on the underlying molecular mechanisms associated with the two dietary treatments. In particular, the data suggests that there may be a crosstalk between ERβ and glycogen synthase kinase 3 signaling pathways that could play a role in conferring ERβ-mediated neuroprotection against AD. Taken together, these results support the therapeutic potential of the phyto-β-SERM formulation for prevention and/or early intervention of AD, and warrants further investigations in human studies.