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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos 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

项目摘要

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）仍然缺乏有效的治疗方法，直接针对β-淀粉样蛋白（Aβ）的药物和过度磷酸化 Tau (pTau) 作为替代方案，开发药物基本上不成功。减轻下游神经退行性反应（独立于 Aβ 和 pTau）可能提供更多值得注意的是，卵巢类固醇产生的丧失显着增加了风险。绝经后妇女的 AD 引起了人们对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 E2 到围绝经期“关键期”的试验取得了更好的总体结果，但仍然同样，选择性雌激素受体调节剂（SERM）也会增加患痴呆症的风险。经典雌激素受体也同样存在问题，因为 ERα 或 ERβ 的慢性激活仍然可能导致相比之下，STX 是一种具有独特特性的新型 SERM。参与 GqMER（Gq 偶联膜雌激素受体），已被证明可以赋予许多 E2 具有神经保护作用，且无副作用。口服 STX 很容易穿过血脑屏障。此外，使用啮齿动物和灵长类动物模型进行的研究。更年期研究表明，STX 治疗可以像 E2 一样有效地恢复体内平衡功能，而无需它副作用（包括男性女性化效应），反映了 GqMER 由 CNS 表达的事实神经元，但不通过大脑中的其他细胞类型或培养的海马体中的外周生殖器官。初步研究发现，STX 可以防止 Aβ 和 pTau 的神经毒性作用。使用淀粉样蛋白病理学的 5XFAD 模型表明口服 STX 还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的正常突触活动来发挥作用，因此，我们将使用它。特征明确的 AD 模型，用于研究 STX 的神经保护机制和功能益处目标 1 将包括一套行为分析（加上事后分析）。神经病理学）以确定口服 STX 在预防 AD 相关疾病方面的有益作用目标 2 将在海马切片制备中采用电生理学方案来研究 STX 减轻影响学习和能力的突触功能丧失的机制 Aim 3 将使用体内多光子成像与随后的共聚焦技术。分析 STX 对线粒体功能和突触棘完整性的神经保护作用的方法 5XFAD 小鼠。