R01 Estrogen therapy and APOE4 risk in Alzheimer's tested in female EFAD mice

R01 在雌性 EFAD 小鼠中测试雌激素治疗和阿尔茨海默病的 APOE4 风险

• 批准号: 9914419
• 负责人: MARY JO LADU
• 金额: $ 7.08万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9914419
• 关键词: ATP binding cassette transporter 1; Ablation; Affect; Alleles; Alternative Therapies; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Animal Model; Apolipoprotein E; Apolipoproteins; Attenuated; Behavior; Benchmarking; Biological Availability; Biological Markers; Brain; Clinical; Cognition; Cognitive deficits; Data; Dementia; Development; Dose; Epidemic; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Estrogen Therapy; Estrogens; Exhibits; Exposure to; FDA approved; Female; Future; Genes; Genotype; Goals; Gynecology; Hot flushes; Human; Impaired cognition; In Vitro; Inflammation; Inflammatory; Link; Measures; Memory; Menopause; Modeling; Mus; Mutation; Neurotoxins; Oral; Outcome; Ovariectomy; Pathology; Pathway interactions; Perimenopause; Pharmacology; Plasma; Postmenopausal Osteoporosis; Postmenopause; Premature Menopause; Premenopause; Presenile Alzheimer Dementia; Prophylactic treatment; Protein Isoforms; Raloxifene; Risk; Role; Safety; Sampling; Selective Estrogen Receptor Modulators; Testing; Therapeutic; Transgenic Mice; Treatment Protocols; Woman; Women' s Health; abeta accumulation; age related; aging brain; apolipoprotein E-4; attenuation; base; cancer chemoprevention; cytokine; dementia risk; design; drug discovery; familial Alzheimer disease; genetic risk factor; improved; in vitro Assay; in vitro Model; in vivo; lifetime risk; male; malignant breast neoplasm; mitochondrial dysfunction; mouse model; nanomolar; novel; pre-clinical; programs; response; sex; virtual; young woman

The gene that controls expression of the apolipoprotein ε4 allele, APOE4, is the greatest genetic risk factor for Alzheimer's disease (AD), increasing risk up to 15-fold compared to APOE3. Although this risk, associated with enhanced amyloid-β (Aβ) accumulation, was discovered over 20 years ago, it has rarely been the focus of therapeutic approaches; even less so, the critical link between female sex and the APOE4-induced risk for dementia and AD. Female (♀) APOE4 carriers have a greater lifetime risk for developing AD, an increased rate of cognitive decline and accelerated accumulation of Aβ compared to male (♂) APOE4 carriers, data consistent with observations in ♀ and ♂ familial AD (FAD) transgenic mice. Estradiol (E2) would appear to be key to this vulnerability: ablation of circulating E2 in pre-menopausal women by oophorectomy causes later cognitive deficits that are reversed by estrogen therapy (ET). The effects of ET after natural menopause remain controversial, particularly with regard to the “critical window” hypothesis stating that ET is beneficial only in the early menopause window. A further concern is the unfavorable safety profile associated with ET resulting from the Women's Health Initiative studies, requiring the development of safer ET alternatives (alt-ET). The goal of this proposal is to determine the ability of ET and alt-ET to counteract the negative interaction of sex with APOE4 in the novel preclinical EFAD mouse model (expressing human APOE +FAD mutations), establishing both the preferred timing and APOE isoform selectivity of safe alt-ET for therapy or prophylaxis of AD. The EFAD mouse was developed to study the interaction between human h-APOE and AD pathology by introducing the h-APOE genotypes into 5xFAD mice: EFAD mice display advanced pathology in females vs. males and E4FAD vs. E3FAD; and preliminary EFAD data suggests that ET after ovariectomy (OVX) protects against cognitive deficits. Alt-ET to be studied are clinical selective estrogen receptor (ER) modulators (SERMs), raloxifene (Ral) and bazedoxifene (Baz); the clinical Baz/E2 combination; and selective estrogen mimics (SEMs) with attenuated gynecological effects. Aim 1: Establish the efficacy of ET (E2) treatment in OVX ♀EFAD mice with respect to APOE genotype, measuring behavior/memory, apoE and Aβ biomarkers, and AD pathology. Aim 2: Establish the “critical window” for ET in EFAD mice with respect to genotype. Aim 3: Test alt-ET in female EFAD mice as transformational AD therapeutics. Dosing will be defined by measuring brain concentrations related to in vitro Kd and EC50. To probe the roles of ER isoforms, mixed glial cultures from APOE-TR mice, will be studied using selective pharmacological ER-probes. In vitro biomarkers (apoE, Aβ, ABCA1, cytokines) will mirror in vivo biomarkers, allowing correlation with in vivo effects of ET and alt-ET, and development of an in vitro assay for future discovery and optimization of Alt-ET for AD.

控制载脂蛋白ε4等位基因表达的基因APOE4是最大的遗传风险因素 与APOE3相比，阿尔茨海默氏病（AD）的风险高达15倍。尽管这种风险与 在20年前发现了增强的淀粉样蛋白β（Aβ）积累，这很少是 治疗方法；女性性别与APOE4引起的风险之间的关键联系更少。 痴呆和广告。女性（♀）APOE4载体的终身风险更大，率提高了 与雄性（♂）APOE4载体相比，Aβ的认知能力下降和加速积累，数据一致 在♀和♂家族AD（FAD）转基因小鼠中观察到。雌二醇（E2）似乎是这样的关键 脆弱性：卵巢前妇女循环E2的消融卵巢切除术会导致后来的认知缺陷 雌激素疗法（ET）逆转。自然更年期后ET的影响仍然有争议， 特别是关于“关键窗口”的假设，表明ET仅在早期才有好处 更年期窗口。另一个问题是与ET相关的不利安全性。 妇女的健康倡议研究，需要开发更安全的ET替代方案（ALT-ET）。目标的目标 建议是确定ET和Alt-Et抵消性与APOE4的负相互作用的能力 新型的临床前小鼠模型（表达人ApoE +FAD突变），同时建立了 首选的定时和APOE同工型的选择性Alt-IT用于AD治疗或预防。 efad鼠标 通过引入H-apoE来研究人类H-APOE与AD病理学之间的相互作用 5xFAD小鼠的基因型：EFAD小鼠在女性与男性和E4FAD与E4FAD的病理中显示出晚期病理。 e3fad; EFAD的初步数据表明，卵巢切除术后ET（OVX）可防止认知缺陷。 alt-et是临床选择性雌激素受体（ER）调节剂（Serm），雷昔芬（RAL）和 Bazedoxifene（BAZ）；临床BAZ/E2组合；和衰减的选择性雌激素模拟（SEM） 妇科作用。 AIM 1：建立ET（E2）治疗在OVX中的效率 APOE基因型，测量行为/记忆，APOE和Aβ生物标志物以及AD病理学。目标2：建立 EFAD小鼠相对于基因型的ET的“关键窗口”。目标3：在雌性efad小鼠中测试alt-et 变革性广告疗法。剂量将通过测量与体外KD相关的脑浓度来定义 和EC50。为了探测ER同工型的作用，将使用APOE-TR小鼠的混合神经胶质培养物进行研究 选择性药物ER探针。体外生物标志物（APOE，Aβ，ABCA1，细胞因子）将在体内反映 生物标志物，允许与ET和alt-et的体内效应相关，并开发用于体外测定法 AD-ET的未来发现和优化。