Therapeutic targeting a membrane estrogen receptor with a novel non-steroidal compound for Alzheimer's disease

阿尔茨海默病（AD）的有效治疗方法仍然缺乏，直接靶向β-淀粉样蛋白（Aβ）的药物 和过度磷酸化的Tau（pTau）在很大程度上不成功。作为替代方案，开发药物， 减轻下游神经退行性反应（独立于Aβ和pTau）可能提供更多的 有效的治疗策略。值得注意的是，卵巢类固醇产生的损失显着增加的风险， 绝经后妇女的AD，增加了激素替代疗法可用于预防或治疗AD的希望。 不幸的是，临床试验发现，17β-雌二醇（E2）产生不可接受的副作用（包括 增加致癌和血栓形成事件），实际上增加了一些患者患痴呆症的风险。 最近针对E2至围月经期“关键期”的试验总体结果更好，但仍然 会增加患痴呆症的风险同样，选择性雌激素受体调节剂（SERM）靶向 经典的雌激素受体同样存在问题，因为ERα或ERβ的慢性激活仍然会导致 对肿瘤敏感的癌症。相比之下，STX是一种具有独特性质的新型SERM。STX特异性 接合GqMER（Gq偶联膜雌激素受体），其已被证明赋予许多 E2的神经保护作用没有副作用。口服STX很容易穿过血脑屏障， 安全地持续给药。此外，使用啮齿动物和灵长类动物模型的研究表明， 绝经期的研究表明，STX治疗可以像E2一样有效地挽救体内平衡功能， 副作用（包括雄性中的雌性化效应），反映了GqMER由CNS表达的事实 神经元，但不被大脑中的其他细胞类型或外周生殖器官。培养海马 在神经元中，发现STX保护免受Aβ和pTau两者的神经毒性作用。初步研究 使用淀粉样蛋白病理学的5XFAD模型表明，口服STX也可以防止淀粉样蛋白的丢失。 认知功能，部分通过支持大脑中正常的突触活动来发挥作用。因此，我们将使用 充分表征的AD模型，以研究STX在AD中的神经保护机制和功能益处。 三个互补的目标。目标1将包括一套行为分析（加上死后分析 的神经病理学），以确定口服STX在预防AD相关的 神经变性Aim 2将在海马切片制备中采用电生理方案， 研究STX减轻影响学习的突触功能丧失的机制， AD大脑中的记忆AIM 3将使用体内多光子成像结合随后的共聚焦 方法分析STX对线粒体功能和突触棘完整性的神经保护作用。 5XFAD小鼠

Effective treatments for Alzheimer's Disease (AD) are still lacking, and drugs that directly target β-amyloid (Aβ) and hyperphosphorylated Tau (pTau) have been largely unsuccessful. As an alternative, developing drugs that mitigate downstream neurodegenerative responses (independent of Aβ and pTau) might provide a more effective therapeutic strategy. Notably, the loss of ovarian steroid production significantly increases the risk of AD in postmenopausal women, raising hopes that hormone replacement could be used to prevent or treat AD. Unfortunately, clinical trials found that 17β-estradiol (E2) produced unacceptable side effects (including increased oncogenic and thrombotic events), and actually increased the risk of dementia in some patients. More recent trials targeting E2 to a perimenopausal `critical period' had better overall outcomes but still involved an increased risk for dementia. Likewise, selective estrogen receptor modulators (SERMs) targeting classical estrogen receptors are equally problematic, as chronic activation of either ERα or ERβ can still result in hormone-sensitive cancers. In contrast, STX is a novel SERM with unique properties. STX specifically engages GqMER (Gq-coupled membrane estrogen receptor), which has been shown to confer many of the neuroprotective benefits of E2 without its side effects. Oral STX readily crosses the blood-brain barrier and can be safely administered for sustained periods. Moreover, studies using both rodent and primate models of menopause have shown that STX treatment can rescue homeostatic functions as effectively as E2 without its side effects (including feminizing effects in males), reflecting the fact that GqMER is expressed by CNS neurons but not by other cell types in the brain or by peripheral reproductive organs. In cultured hippocampal neurons, STX was found to protect against the neurotoxic effects of both Aβ and pTau. Preliminary studies using the 5XFAD model of amyloid pathology indicate that oral STX can also protect against the loss of cognitive function, acting in part by supporting normal synaptic activity in the brain. Accordingly, we will use this well-characterized AD model to investigate the neuroprotective mechanism and functional benefits of STX in three complementary aims. Aim 1 will include a suite of behavioral assays (coupled with postmortem assays of neuropathology) to determine the beneficial effects of oral STX in protecting against AD-associated neurodegeneration. Aim 2 will employ electrophysiological protocols in hippocampal slice preparations to investigate the mechanisms by which STX mitigates the loss of synaptic functions that affect learning and memory in the AD brain. Aim 3 will use in vivo multiphoton imaging combined with subsequent confocal methods to analyze the neuroprotective effects of STX on mitochondrial function and synaptic spine integrity in the 5XFAD mice.