Modulation of tau pathogenesis by high dietary fat, gender and ApoE isoform

高膳食脂肪、性别和 ApoE 异构体对 tau 蛋白发病机制的调节

基本信息

批准号：
9036260
负责人：
SALLY ANN FRAUTSCHY
金额：
$ 18.9万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
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：
2016-08-15 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9036260
关键词：
Acceleration Affect Age Age of Onset Aging Alzheimer&apos s Disease Alzheimer&apos s disease risk American Amyloid Amyloid beta-Protein Animal Model Apolipoprotein E Binding Cognition Cognitive deficits Data Deposition Development Diet Dietary Fats Disease Progression Economics Elderly Environment Environmental Risk Factor Epidemic Epidemiology FYN gene Fatty acid glycerol esters Female Gender Genes Genetic Genomics Genotype Gonadal Steroid Hormones High Fat Diet Human Infusion procedures Investigation Late Onset Alzheimer Disease Link MAPK8 gene Membrane Microdomains Methods Modeling Mus Nerve Degeneration Neurites Neurofibrillary Tangles Omega-3 Fatty Acids Outcome Pathogenesis Pathology Pathway interactions Patients Phosphoric Monoester Hydrolases Phosphotransferases Physical Exercise Play Population Protein Isoforms Protein Phosphatase 2A Regulatory Subunit PR53 Proteins Proto-Oncogene Proteins c-akt Public Health Regulation Reporting Resources Risk Risk Factors Role Senile Plaques Severity of illness Site Specificity Synapses Tauopathies Testing Transgenes Transgenic Mice Transgenic Model Translations Western World Work abeta deposition aging population apolipoprotein E-3 apolipoprotein E-4 drug testing feeding genetic risk factor genome wide association study good diet high risk inhibitor/antagonist insight insulin signaling loss of function male model development mutant neuroimaging neuroinflammation new therapeutic target novel promoter public health relevance response saturated fat sex tau Proteins tau aggregation tau expression tau interaction tau-protein kinase treatment center western diet

项目摘要

DESCRIPTION (provided by applicant): Genes, environment and gender influence Alzheimer (AD) risk, but the development of models to investigate common risk factors like age, ApoE4, high fat and gender on tauopathy and their interaction is surprisingly limited. Tau, the main tangle protein, can be downstream of β-amyloid (Aβ), the main constituent of the neuritic plaque, but tau can accumulate independent of Aβ in response to other factors including neuroinflammation. High saturated fat Western diet is an AD risk factor that increases neuroinflammation and tau expression, independent of Aβ deposition. High saturated fat diet increases human ApoE4 risk and src/fyn kinase activation in lipid rafts upstream of JNK activation that is opposed by dietary n-3 fatty acids. In our preliminary data high fat increased src/fyn site pY307 PP2A inactivation, pJNK and ptau. Integrated genomic analysis of human ApoE4 data reveals increased FYN kinase at the center of an E4 network hub. Although E4 can modulate Aβ deposition, female E4 carriers have much higher risk, now confirmed in recent AD Neuroimaging Initiative (ADNI) data, that also finds that female E4 carriers have more CSF tau -irrespective of Aβ. This argues that E4/gender/tau interactions contribute to E4 gender risk. However, there are no tauopathy models currently available to test gender risk mechanisms or treatments and interactions involving E4 and tau. Introducing an ApoEKO background into a mutant tauopathy model increased the number of ptau positive neurites, suggesting loss of function of ApoE accelerates tauopathy. In Aim 1 we will cross the hutauTg mouse onto the ApoE KO background (EKO-TAU) to determine the impact on tau pathogenesis, influence of gender and gonadectomy to emulate loss of gonadal steroids with aging. In Aim 2 we cross human TR ApoE3 or ApoE4 into this EKO-TAU line, to generate the E3TAU and E4TAU model, creating resources for the exploration of understanding tau-ApoE isoform associations, independent of (or dependent on) Aβ. This aim will determine ApoE modulatory and interactive effects of gender and high fat on tau pathogenesis. Since our preliminary data support a role for saturated fat/src/fyn/PP2A/JNK and AKT/GSK3 pathway and gender effects, Aim 3 uses a pure tauopathy model to determine the effects of Western diet (17% fat) and gender and their interaction on tau pathogenesis, neuroinflammation, src/fyn, RACK1 and PP2Aand AKT/GSK3 regulation during aging and independent of Aβ. We will evaluate synaptic and cognitive deficits, changes in activity of tau kinases including fyn, neuroinflammation and our focus, the dysregulation of PP2A. Completion of these aims will have broad implications, including development of a novel model for ApoE-tau interactions, demonstrating isoform-differences in tau accumulation, kinase regulation and neuroinflammation and ApoE x gender- specificity for high fat induced tauopathy. The new models will permit testing novel therapeutics targeting ApoE dependent effects on tau. This is high impact because of compelling data that both AD and ApoE4 modulate PP2A activity-now linked to tauopathy and disease progression.

描述（由适用提供）：基因，环境和性别影响阿尔茨海默氏症（AD）风险，但是开发了调查常见风险因素（例如年龄，APOE4，高脂和性别）的危险因素的模型及其相互作用非常有限。 tau是主要的缠结蛋白，可以是β-淀粉样蛋白（Aβ）的下游，β-淀粉样蛋白是神经质斑块的主要成分，但tau可以累积与Aβ的积累，以响应其他因素，包括神经炎症。高饱和脂肪西部饮食是AD危险因素，它增加了神经炎症和TAU表达，而与Aβ沉积无关。高饱和脂肪饮食增加了JNK激活上游的脂质筏中的人类APOE4风险和SRC/FYN激酶激活，这与饮食中的N-3脂肪酸相反。在我们的初步数据中，高脂肪增加了SRC/FYN位点PY307 PP2A灭活，PJNK和PTAU。人类APOE4数据的综合基因组分析表明，在E4网络中心的FYN激酶增加。尽管E4可以调节Aβ的沉积，但雌性E4载体的风险更高，现在在最近的AD神经影像学计划（ADNI）数据中得到了证实，这也发现雌性E4载体对Aβ的CSF TAU具有更多的影响。这是E4/性别/TAU相互作用有助于E4性别风险的论点。但是，目前尚无可用于测试涉及E4和TAU的性别风险机制或治疗方法以及相互作用的tauopathy模型。将apoeko背景引入突变的陶氏病模型增加了PTAU阳性神经运动的数量，表明APOE的功能丧失了加速tauopathy。在AIM 1中，我们将越过Hutautg小鼠在APOE KO背景（Eko-Tau）上，以确定对Tau发病机理的影响，性别和性别切除术对模仿衰老的性腺定型物的丧失的影响。在AIM 2中，我们将人类TR APOE3或APOE4穿过此EKO-TAU线，以生成E3TAU和E4TAU模型，为探索理解Tau-apoe同工型关联的探索创造了资源，与Aβ无关（或依赖性）。该目标将确定性别和高脂肪对Tau发病机理的APOE调节和互动效应。 Since our preliminary data support a role for saturated fat/src/fyn/PP2A/JNK and AKT/GSK3 pathway and gender effects, Aim 3 uses a pure tauopathy model to determine the effects of Western diet (17% fat) and gender and their interaction on tau pathogenesis, neuroinflammation, src/fyn, RACK1 and PP2Aand AKT/GSK3 regulation在衰老期间独立于Aβ。我们将评估合成和认知缺陷，tau激酶的活性变化，包括FYN，神经炎症和我们的重点，PP2A的失调。这些目标的完成将具有广泛的含义，包括开发一种新型的APOE-TAU相互作用模型，证明了Tau积累，激酶调节和神经炎症的同工型差异以及高脂肪诱导的Tauopathy的APOE X性别特异性。新模型将允许测试针对APOE依赖对TAU的新型治疗。这是高影响力，因为AD和APOE4都在调节pp2a活性和疾病进展相关的pp2a活性。