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

使用新型非甾体化合物靶向膜雌激素受体治疗阿尔茨海默病

• 批准号: 10670490
• 负责人: PHILIP F COPENHAVER
• 金额: $ 76.69万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10670490
• 关键词: Acute; Affect; Age; Alzheimer associated neurodegeneration; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid beta-42; Amyloid beta-Protein; Animal Model; Animals; Autopsy; Behavioral Assay; Biological Assay; Biological Markers; Blood - brain barrier anatomy; Blood Coagulation Factor; Brain; Brain Pathology; Cells; Cephalic; Cerebrospinal Fluid; Chronic; Clinical Trials; Cognitive; Coupled; Dementia; Disease; Electrophysiology (science); Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Estrogen Therapy; Estrogens; Event; Female; Feminization; Formulation; Glial Fibrillary Acidic Protein; Gliosis; Glutamates; Goals; Health; Hippocampus (Brain); Hormone replacement therapy; Hormones; Human; Impaired cognition; Impairment; Intervention; Ischemia; Label; Laboratories; Learning; Ligands; Light; Link; Liver; Long-Term Potentiation; Malignant Neoplasms; Mediating; Membrane; Memory; Memory impairment; Menopause; Methods; Mitochondria; Modeling; Monitor; Mus; Nerve Degeneration; Neurons; Oncogenic; Oral; Outcome; Ovarian; Pacemakers; Pathogenesis; Pathway interactions; Patients; Perimenopause; Peripheral; Pharmaceutical Preparations; Physiology; Plasma; Postmenopause; Preparation; Prevention; Primates; Production; Progestins; Property; Protocols documentation; Publishing; Receptor Signaling; Rodent; Role; Sampling; Selective Estrogen Receptor Modulators; Slice; Steroids; Synapses; Synaptic Transmission; System; Testing; Therapeutic; Thrombosis; Treatment Protocols; Vertebral column; Woman; Work; abeta accumulation; abeta oligomer; abeta toxicity; adverse outcome; age related; alternative treatment; amyloid pathology; base; cell type; cognitive benefits; cognitive function; cohort; confocal imaging; critical period; dementia risk; density; effective therapy; excitotoxicity; experimental study; hyperphosphorylated tau; in vivo; male; mouse model; multiphoton imaging; neurofilament; neuroinflammation; neuron loss; neuronal excitability; neuropathology; neuroprotection; neurotoxic; novel; older women; patch clamp; pre-clinical assessment; preservation; prevent; protective effect; reproductive organ; response; sex; side effect; small molecule; synaptic function; targeted treatment; tau Proteins; tau-1; therapeutic target; therapeutically effective; thrombotic; transmission process; treatment strategy

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.

阿尔茨海默病(AD)的有效治疗方法仍然缺乏，直接针对β-淀粉样蛋白(Aβ)的药物 而过度磷酸化的Tau(Ptau)在很大程度上并不成功。作为另一种选择，开发出 减轻下游神经退行性反应(独立于Aβ和PTAU)可能提供更多 有效的治疗策略。值得注意的是，卵巢类固醇分泌的丧失显著增加了 绝经后妇女的AD，增加了激素替代可用于预防或治疗AD的希望。 不幸的是，临床试验发现17β-雌二醇(E2)产生了不可接受的副作用(包括 增加致癌和血栓事件)，实际上增加了一些患者患痴呆症的风险。 最近针对围绝经期“关键期”的E2试验总体结果较好，但仍 导致患痴呆症的风险增加。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有问题，因为ERα或ERβ的慢性激活仍然可能导致 激素敏感型癌症。相比之下，STX是一种具有独特性质的新型SERM。特别是STX 与GqMER(Gq偶联的膜雌激素受体)结合，已被证明赋予许多 雌二醇的神经保护作用，无副作用。口服STX很容易通过血脑屏障，可以 持续安全地给药。此外，使用啮齿动物和灵长类动物模型进行的研究 更年期的研究表明，STX治疗可以像没有雌激素的情况下一样有效地恢复体内平衡功能 副作用(包括男性的女性化效应)，反映了GqMER由CNS表达的事实 神经元，而不是大脑中的其他细胞类型或外围生殖器官。在培养的海马区 研究发现，STX对Aβ和PTAU的神经毒性效应均有保护作用。初步研究 使用淀粉样蛋白病理的5XFAD模型表明，口服STX也可以保护 认知功能，部分通过支持大脑中正常的突触活动而起作用。因此，我们将使用这一点 应用AD模型研究STX对AD的神经保护机制和功能益处 三个互补的目标。AIM 1将包括一套行为分析(结合尸检 神经病理学)以确定口服STX在预防AD相关疾病方面的有益效果 神经退行性变。AIM 2将在海马片制备中使用电生理方案 研究STX减轻影响学习和学习的突触功能丧失的机制 AD大脑中的记忆。AIM 3将使用活体多光子成像结合后续的共聚焦 方法分析链脲佐菌素对大鼠脑线粒体功能和突触棘完整性的神经保护作用。 5XFAD小鼠。