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APOEε4等位基因是阿尔茨海默氏病（AD）的最大遗传危险因素并且与加速的淀粉样蛋白β肽（Aβ）累积均与淀粉样蛋白和可溶性有关寡聚Aβ（OAβ），后者认为是近端神经毒素。重要的是，女性ε4载体具有更大的发展AD的终生风险，认知能力下降的速度增加和Aβ的加速积累与男性载体相比。同样，女性家庭广告（FAD）-TG小鼠具有更大的认知缺陷，并且与雄性小鼠相比，Aβ病理增加。 APOE4和AD风险之间的联系可能是多因素的，并且仍然很了解；而女性ε4载体的风险增加实际上是出乎意料的。作为零星的广告约占病例的98％，而年龄为关键风险因素，该提案的UH2阶段将测试老化的EFAD小鼠发展了深刻的AD病理，这一假说受APOE的影响很大基因型和性别。为了研究人类APOE（H-APOE）与AD病理学之间的相互作用，我们发展了通过将H-APOE引入5XFAD-TG小鼠，EFAD小鼠。到6个月（M），E4FAD小鼠的Aβ-和与E3FAD相比，TAU-PATHology，神经炎症和认知缺陷。在E4FAD与E3FAD和女性与男性，淀粉样蛋白和固体Aβ（Aβ42和OAβ）的水平更大，APOE/Aβ复合物降低。将这些观察结果统一为可检验的假设的关键部分是 apoe。 APOE在E4FAD与E3FAD大脑和女性与男性中的脂化较少。在人脑和CSF中，和EFAD小鼠脑，APOE脂质与固体Aβ负相关。对于UH3阶段，我们数据支持降低APOE脂化的假设导致APOE/Aβ络合物的水平降低，固体Aβ，合成损失，记忆和认知缺陷和痴呆症的效率低下。 UH2阶段： AIM 1：为18M EFAD小鼠建立育种计划，并对AD病理进行基准测试。（n = 12）：apoe4♀>apoE4♀≥APOE3♀>apoe4♀。到第二年底，措施将包括MWM 行为，免疫组织化学（IHC）的AD病理学和生物化学（BC），包括APOE，OAβ，OAβ， Aβ42。 UH3阶段：衰老的EFAD小鼠是影响人类AD病理学因素的可行模型，特别是APOE基因型和性别，因此提供了测试前瞻性治疗干预措施的模型和机械假设，包括我们的“ APOE脂质假设”？目标2。建立10m，14m（中间）年龄）和18m（年龄）EFAD小鼠同类群来通过详细的行为分析和与6M（成人）（ε3和ε4；♂和♀）进行比较的组织。分析将包括多个认知测试，IHC 用于Aβ-和TAU-PATHOLOGY神经炎症和神经县，以及BC的apoE和 Aβ，APOE脂质以及OAβ，Aβ42，APOE和APOE/Aβ的水平。广告临床试验的失败询问临床前AD-TG小鼠模型的预测有效性，该模型缺乏H-APOE，这是AD的主要遗传风险因素。但是，广告的最大风险因素是年龄。老年EFAD小鼠将解决这两个关键危险因素。