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.

仍缺乏对阿尔茨海默氏病（AD）的有效治疗方法，直接靶向β-淀粉样蛋白（Aβ）的药物和高磷酸化的tau（PTAU）在很大程度上没有成功。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）可能会提供更多有效的治疗策略。值得注意的是，卵巢类固醇产量的损失显着增加了绝经后妇女的广告，提高希望可以使用替换赛车来预防或治疗广告。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（包括增加致癌事件和血小板事件），实际上增加了某些患者的痴呆症风险。最新针对E2到围绝经内的“关键时期”的试验具有更好的总体结果涉及痴呆症的风险增加。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的慢性激活仍可能导致在同性敏感的癌症中。相反，STX是具有独特特性的新型Serm。特别是STX 参与GQMER（GQ耦合的膜雌激素受体），已显示出许多 E2的神经保护益处而没有其副作用。口服STX容易越过血脑屏障，可以可以安全地管理持续时期。此外，使用啮齿动物和灵长类动物模型的研究更年期表明，STX治疗可以像E2一样有效地拯救体内稳态功能副作用（包括男性的女性化效应），反映了GQMer由中枢神经系统表达的事实神经元，但不是大脑中的其他细胞类型或周围生殖器官。在培养的海马发现神经元的STX可预防Aβ和PTAU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也可以防止损失认知功能，部分作用是由大脑中的正常突触活动作用。根据，我们将使用此特征良好的AD模型，以研究STX在中的神经保护机制和功能益处三个完整的目标。 AIM 1将包括一套行为测定套件（与验尸测定相结合神经病理学），以确定口服STX在保护AD相关的有益作用神经变性。 AIM 2将在海马切片制剂中采用电生理方案研究STX减轻影响学习和的突触功能丧失的机制广告大脑中的记忆。 AIM 3将使用体内多光子成像与随后的共聚焦分析STX对线粒体功能和突触脊柱完整性的神经保护作用的方法 5xfad小鼠。