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Aged EFAD mice as a model for the effects of APOE and sex on AD pathology

老年 EFAD 小鼠作为 APOE 和性别对 AD 病理学影响的模型

基本信息

批准号：
9978939
负责人：
MARY JO LADU
金额：
$ 23.99万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
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：
2016-09-30 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9978939
关键词：
AD transgenic mice ATP binding cassette transporter 1 Address Adult Age Aging Alleles Alzheimer&apos s Disease Alzheimer&apos s disease care Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease risk Amino Acids Amyloid Amyloid beta-42 Amyloid beta-Protein Apolipoprotein E Behavior Benchmarking Biochemical Biochemistry Brain Breeding Cell Count Clinical Trials Cognition Cognitive deficits Complex Data Dementia Development Disease Progression Epidemic Exhibits Failure Female Formic Acids Foundations Gel Genotype Hippocampus (Brain)Human Immunohistochemistry Impaired cognition Link Lipids Lipoproteins Measures Memory impairment Modeling Mus Mutation National Institute on Aging Neurons Neurotoxins Pathology Phase Protein Isoforms Proteins Protocols documentation RXR Risk Risk Factors Role Senile Plaques Synapses Testing Therapeutic Intervention Tissues Transgenic Mice Triton X100 United States Woman abeta accumulation age effect aged apolipoprotein E-3 apolipoprotein E-4 astrogliosis base behavior test cognitive testing cohort cost extracellular familial Alzheimer disease frontal lobe genetic risk factor human disease lifetime risk male men middle age mouse model neglect neuroinflammation novel postsynaptic pre-clinical programs prospective test sex tau Proteins virtual

项目摘要

The APOE ε4 allele of apolipoprotein E (apoE) is the greatest genetic risk factor for Alzheimer's disease (AD) and is associated with accelerated amyloid-β peptide (Aβ) accumulation both as amyloid and soluble oligomeric Aβ (oAβ), the latter considered a proximal neurotoxin. Importantly, female ε4 carriers have a greater lifetime risk for developing AD, an increased rate of cognitive decline and accelerated accumulation of Aβ compared to male carriers. Similarly, female familial AD (FAD)-Tg mice have greater cognitive deficits and increased Aβ pathology than male mice. The link between APOE4 and AD risk is likely multi-factorial and remains poorly understood; while the increased risk for female ε4 carriers remains virtually unexplored. As sporadic AD represents ∼98% of cases, with age the key risk factor, the UH2 phase of this proposal will test the hypothesis that aged EFAD mice develop profound AD pathology, significantly influenced by APOE genotype and sex. To study the interaction between human APOE (h-APOE) and AD pathology, we developed EFAD mice by introducing h-APOE into 5xFAD-Tg mice. By 6 months (M), E4FAD mice have greater Aβ- and tau-pathology, neuroinflammation and cognitive deficits compared to E3FAD. In E4FAD vs. E3FAD, and females vs. males, the levels of amyloid and soluble Aβ (Aβ42 and oAβ) are greater and apoE/Aβ complex lower. The critical component uniting these observations into a testable hypothesis is the lipidation state of apoE. ApoE is less lipidated in E4FAD vs. E3FAD brains and in females vs. males. In human brain and CSF, and EFAD mouse brain, apoE lipidation negatively correlates with soluble Aβ. Thus, for the UH3 phase, our data support the hypothesis that reduced apoE lipidation results in reduced levels of apoE/Aβ complex, inefficient clearance of soluble Aβ, synaptic loss, memory and cognitive deficits, and dementia. UH2 Phase: Aim 1: Establish breeding program for 18M EFAD mice and perform benchmark testing for AD pathology. (N=12): APOE4♀ > APOE4♂ ≥ APOE3♀ > APOE4♂. By the end of Year 2, measures will include MWM for behavior, AD pathology by immunohistochemistry (IHC), and biochemistry (BC) including levels of apoE, oAβ, Aβ42. UH3 Phase: Are aging EFAD mice a viable model for the factors effecting AD pathology in humans, particularly APOE genotype and sex, thus providing a model for testing prospective therapeutic interventions and mechanistic hypotheses, including our “apoE lipidation hypothesis”? Aim 2. Establish 10M, 14M (middle age) and 18M (aged) EFAD mouse cohorts to define disease progression by detailed analysis of behavior and tissue for comparison with 6M (adult) (ε3 and ε4; ♂ and ♀). Analyses will include multiple cognitive tests, IHC for Aβ- and tau-pathology neuroinflammation and neuron counts, and BC for extraction profiles of apoE and Aβ, apoE lipidation, and levels of oAβ, Aβ42, apoE, and apoE/Aβ. The failure of AD clinical trials questions the predictive validity of preclinical AD-Tg mouse models that lack h-APOE, the major genetic risk factor for AD. However, the greatest risk factor for AD is age; aged EFAD mice will address both these critical risk factors.

载脂蛋白E（apoE）的ε4等位基因是阿尔茨海默病（AD）的最大遗传危险因素并与淀粉样蛋白和可溶性β-淀粉样蛋白（Aβ）的加速积累有关。寡聚体Aβ（oAβ），后者被认为是近端神经毒素。重要的是，女性ε4携带者有更大的发生AD的终生风险、认知能力下降率增加和Aβ积累加速与男性携带者相比。类似地，雌性家族性AD（FAD）-Tg小鼠具有更大的认知缺陷， Aβ病理学增加。APOE 4和AD风险之间的联系可能是多因素的，目前尚不清楚;而女性ε4携带者的风险增加几乎尚未探索。作为散发性AD占病例的98%，年龄是关键风险因素，本提案的UH 2阶段将测试老年EFAD小鼠发生严重AD病理学，受APOE显著影响的假设基因型和性别为了研究人类载脂蛋白E（h-APOE）和AD病理之间的相互作用，我们开发了一种新的方法，通过将h-APOE引入5xFAD-Tg小鼠中，在EFAD小鼠中进行。到6个月时（M），E4 FAD小鼠具有更大的Aβ-和与E3 FAD相比，tau病理学、神经炎症和认知缺陷。在E4 FAD与E3 FAD中，以及与男性相比，女性的淀粉样蛋白和可溶性Aβ（Aβ42和oAβ）水平更高，apoE/Aβ复合物低于将这些观察结果统一为可检验假设的关键组成部分是 apoE ApoE在E4 FAD与E3 FAD脑中以及在女性与男性中脂化较少。在人脑和脑脊液中，和EFAD小鼠脑中，apoE脂化与可溶性Aβ呈负相关。因此，对于UH 3阶段，我们数据支持apoE脂化作用降低导致apoE/Aβ复合物水平降低的假设，可溶性Aβ清除效率低下、突触丧失、记忆和认知缺陷以及痴呆。UH 2阶段：目的1：建立18 M EFAD小鼠的繁殖程序并进行AD病理学的基准测试。（N=12）：APOE 4 β> APOE 4 β ≥ APOE 3 β> APOE 4 β。到第二年年底，措施将包括MWM，行为、AD病理学（免疫组织化学（IHC））和生物化学（BC），包括apoE、oAβ水平， Aβ42 UH 3阶段：老年EFAD小鼠是否是影响人类AD病理学因素的可行模型，特别是APOE基因型和性别，从而提供了一个模型，用于测试前瞻性的治疗干预措施和机械假说，包括我们的“载脂蛋白E脂化假说”？目标二。建立10 M、14 M（中间年龄）和18个月（年龄）EFAD小鼠组，通过详细分析行为和组织用于与6 M（成人）进行比较（ε3和ε4; ε 2和ε 3）。分析将包括多种认知测试，IHC 用于Aβ和tau病理学神经炎症和神经元计数，BC用于apoE和 Aβ、apoE脂化和oAβ、Aβ42、apoE和apoE/Aβ水平。AD临床试验的失败质疑了缺乏h-APOE（AD的主要遗传风险因素）的临床前AD-Tg小鼠模型的预测有效性。然而，AD的最大风险因素是年龄;老年EFAD小鼠将解决这两个关键风险因素。