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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）的有效治疗方法仍然缺乏，而直接靶向β-淀粉样蛋白（Aβ）的药物仍然缺乏。