APOE genotype and sex dependent effects of 17-alpha-estradiol on AD pathology

APOE 基因型和 17-α-雌二醇对 AD 病理学的性别依赖性影响

基本信息

批准号：
9266737
负责人：
KEBRETEN F MANAYE
金额：
$ 7.55万
依托单位：
HOWARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9266737
关键词：
APP-PS1 Address Adult Age Age-associated memory impairment Alleles Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyloid Amyloid beta-Protein Anti-Inflammatory Agents Anti-inflammatory Apolipoprotein E Astrocytes Atrophic Autopsy Behavioral Biological Assay Brain Brain Stem Brain region Clinical Research Cognitive Collaborations Data Dementia Deposition Drug Approval Economic Burden Effectiveness Elderly Elderly man Elderly woman Emotional Enzymes Estradiol Estrogen Replacement Therapy Estrogens Evaluation Excision Family Female Gender Genes Genotype Gonadal Steroid Hormones Health Hippocampal Formation Hippocampus (Brain)Human Immunoassay Impaired cognition Incidence Inflammation Inflammatory Isomerism Knock-in Knock-in Mouse Learning Link Long-Term Potentiation Measures Mediating Memory Menopause Microglia Modeling Mus Neurofibrillary Tangles Neurons Outcome Pathologic Pathology Patients Peptides Peripheral Placebos Population Postmenopause Prior Therapy Public Health Reproductive Physiology Risk Factors Role Senile Plaques Site Societies Source Staining method Stains Structure of molecular layer of cerebellar cortex Synapses Synaptic plasticity Technology Testing Therapeutic Toxic effect Translating Universities Woman Women&apos s Health base computerized cytokine density effective therapy experimental study extracellular hippocampal atrophy hippocampal pyramidal neuron hyperphosphorylated tau in vivo locus ceruleus structure male men middle age mouse model nerve injury neurite growth neurogenesis neuroinflammation neuron loss noradrenergic novel novel strategies performance tests prevent public health relevance sex subcutaneous translational approach treatment strategy xenoestrogen

项目摘要

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is characterized at post-mortem examination by high densities of ß-amyloid (Aß)-containing plaques and extensive neurogliosis in cortical brain regions, with severe loss of neurons, including the pyramidal neurons in the CA sub-regions of the hippocampus and noradrenergic neurons in the locus coeruleus (LC). AD is the most common cause of elderly dementia and women have a higher incidence of AD than men. The gradual loss of sex steroid hormones may contribute to age associated cognitive decline. A neuroprotective role of estrogens in murine models has been established. Specifically, 17-β-estradiol has been shown to stimulate enhanced synaptic plasticity, neurite growth, hippocampal neurogenesis and long-term potentiation. However, its effects on peripheral targets in humans limit the usefulness of β-E2 as a potential therapy. Negative outcomes from the large Women's Health Initiative Memory Study (WHIMS), a clinical study using β-E2 highlight the dire need to analyze non-feminizing estrogens. Recently, we discovered that 17-α-estradiol (α-E2), an isomer of 17β-estradiol, appear to mitigate the severiy of neuron loss, amyloid burden, and neuroglial proliferation in adult dtg APP/PS1 mice. To begin to address this hypothesis in-vivo, we propose to identify mechanisms for the neuroprotective effects of α-E2 in APOE knock in (APOE3 and APOE4) and 5x FAD mice. Using equal numbers of both male and female mice, we will deliver αE2 over sixty days via subcutaneous pellets. Sacrifice and brain removal will follow to identify if neuroprotective effects of αE2 are mediated in a sex and/or apoE genotype dependent manner. Endpoints for these studies will be computerized stereology to quantify neuron loss in CA1 and LC, amyloid burden and neuroglial proliferation in the hippocampal formation; and enzyme-linked immunoassays to quantify levels of Aß peptides and pro-inflammatory cytokines in hippocampal molecular layers. Taken together, these experiments will provide perhaps the most direct in-vivo assessment of cellular sites for αE2's neuroprotective effects in APOE knock-in (APOE3 and APOE4) and 5x FAD mice. Results will assess whether αE2 deserves further study as a potential strategy for the therapeutic management of AD in middle-aged and elderly men and women.

DESCRIPTION (provided by application): Alzheimer's disease (AD) is characterized at post-mortem examination by high densities of ß-amyloid (Aß)-containing plaques and extensive neurogliosis in cortical brain regions, with severe loss of neurons, including the pyramidal neurons in the CA sub-regions of the hippocampus and noradrenergic neurons in the locus coeruleus （LC）。 AD是老年痴呆症的最常见原因，女性的AD发病率高于男性。性别立体骑马的年级丧失可能导致与年龄相关的认知下降。已经建立了进化在鼠模型中的神经保护作用。具体而言，已证明17-β-雌二醇可以刺激增强的突触可塑性，神经根，海马神经发生和长期潜力。但是，它对人类外围靶标的影响限制了β-E2作为一种潜在疗法的实用性。大型妇女健康倡议记忆研究（WHIMS）的负面结果是，使用β-E2的临床研究突出了可迫切需要分析非嘲笑发展的需求。最近，我们发现17-α-雌二醇（α-E2）是17β-雌二醇的异构体，似乎可以减轻成人DTG APP/PS1小鼠中神经元丧失，淀粉样蛋白伯嫩和神经凝胶增殖的严重性。为了开始解决这一假设，我们建议识别α-e2在APOE敲击（APOE3和APOE4）和5x FAD小鼠中的神经保护作用的机制。使用相等数量的雄性和雌性小鼠，我们将在六十天内通过皮下颗粒传递αE2。牺牲和清除大脑将遵循αE2的神经保护作用是否介导以性别和/或APOE基因型依赖性方式。这些研究的终点将是计算机化的立体学，以量化CA1和LC中的神经元丧失，淀粉样蛋白伯嫩和神经胶质扩散在海马形成中；和酶联的免疫测定法，以量化海马分子层中Aß肽和促炎性细胞因子的水平。综上所述，这些实验将为APOE敲入（APOE3和APOE4）和5x FAD小鼠的αE2神经保护作用提供最直接的体内评估。结果将评估αE2是否值得进一步研究，作为中年和老年男女AD治疗管理的潜在策略。