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

• 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
• 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' s Disease; Alzheimer' 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' 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

 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.

 描述(申请人提供)：阿尔茨海默病(AD)的尸检特征是高密度的含淀粉样蛋白的斑块和皮质脑区广泛的神经胶质细胞增生，神经元严重丧失，包括海马区CA亚区的锥体神经元和蓝斑(LC)的去甲肾上腺素能神经元。AD是老年痴呆症最常见的原因，女性AD的发病率高于男性。性类固醇激素的逐渐丧失可能会导致与年龄相关的认知能力下降。雌激素在小鼠模型中的神经保护作用已经确立。具体地说，17-β-雌二醇已被证明能刺激增强的突触可塑性、轴突生长、海马神经发生和长时程增强。然而，它对人类外周靶点的影响限制了β-E2作为一种潜在治疗方法的有效性。大型女性健康倡议记忆研究(Whims)的负面结果，这是一项使用β-E2的临床研究，突显了分析非女性化雌激素的迫切需要。最近，我们发现17-α-雌二醇(17-α-E_2)是17-β-雌二醇的一个异构体，似乎可以减轻成年dtg app/ps_1小鼠神经元丢失、淀粉样蛋白负荷和神经胶质细胞增殖的严重程度。为了在体内解决这一假说，我们建议确定α-E2对载脂蛋白E敲入(载脂蛋白3和载脂蛋白4)和5x FAD小鼠的神经保护作用的机制。使用相同数量的雄性和雌性小鼠，我们将通过皮下给药颗粒在60天内传递αE2。随后将进行牺牲和脑切除，以确定是否介导了αE2的神经保护作用 以性别和/或载脂蛋白E基因依赖的方式。这些研究的终点将是计算机化的体视学，以量化CA1和LC中的神经元丢失、淀粉样蛋白负荷和海马结构中的神经胶质细胞增殖；以及酶联免疫分析，以定量海马区分子层中的多肽和促炎细胞因子的水平。综上所述，这些实验将提供可能是最直接的体内评估细胞位置的αE2‘S神经保护作用的敲入(载脂蛋白3和载脂蛋白4)和5x FAD小鼠。结果将评估αE2是否值得进一步研究，作为治疗中老年男性和女性AD的潜在策略。