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

 描述（由申请人提供）：基因、环境和性别影响阿尔茨海默病（AD）风险，但研究常见风险因素（如年龄、ApoE 4、高脂肪和性别）对tau蛋白病及其相互作用的模型的开发令人惊讶地有限。主要缠结蛋白Tau可以位于β-淀粉样蛋白（Aβ）的下游，β-淀粉样蛋白是神经炎斑的主要成分，但是Tau可以响应于包括神经炎症在内的其他因素而独立于Aβ积累。高饱和脂肪的西方饮食是AD的一个危险因素，增加神经炎症和tau蛋白表达，独立于Aβ沉积。高饱和脂肪饮食增加人ApoE 4风险和JNK激活上游脂筏中src/fyn激酶激活，这与饮食n-3脂肪酸相反。在我们的初步数据中，高脂肪增加src/fyn位点pY 307 PP 2A失活，pJNK和ptau。人类ApoE 4数据的综合基因组分析揭示了E4网络中心的FYN激酶增加。虽然E4可以调节Aβ沉积，但女性E4携带者的风险要高得多，最近的AD神经影像学倡议（ADNI）数据证实了这一点，该数据还发现女性E4携带者具有更多的CSF tau -与Aβ无关。这表明E4/性别/tau相互作用导致E4性别风险。然而，目前还没有tau蛋白病模型可用于测试性别风险机制或涉及E4和tau的治疗和相互作用。将ApoEKO背景引入突变体tau蛋白病模型增加了ptau阳性神经突的数量，表明ApoE功能丧失加速了tau蛋白病。在目标1中，我们将hutauTg小鼠与ApoE KO背景（EKO-TAU）杂交，以确定对tau发病机制的影响、性别和性腺切除术的影响，以模拟性腺类固醇随着衰老的损失。在目的2中，我们将人TR ApoE 3或ApoE 4与EKO-TAU系杂交，以产生E3 TAU和E4 TAU模型，为探索理解独立于（或依赖于）Aβ的tau-ApoE亚型关联创造资源。这一目的将确定性别和高脂肪对tau发病机制的ApoE调节和交互作用。由于我们的初步数据支持饱和脂肪/src/fyn/PP 2A/JNK和AKT/GSK 3通路和性别效应的作用，目的3使用纯tau蛋白病模型来确定西方饮食（17%脂肪）和性别的影响以及它们在衰老过程中对tau蛋白发病机制、神经炎症、src/fyn、RACK 1和PP 2A以及AKT/GSK 3调节的相互作用，并且独立于Aβ。我们将评估突触和认知缺陷，tau激酶活性的变化，包括fyn，神经炎症和我们的重点，PP 2A的失调。这些目标的完成将具有广泛的意义，包括开发ApoE-tau相互作用的新模型，证明tau积累、激酶调节和神经炎症中的同种型差异以及高脂肪诱导的tau病变的ApoE x性别特异性。新模型将允许测试靶向ApoE对tau依赖性作用的新型疗法。这是高度影响，因为令人信服的数据表明AD和ApoE 4都调节PP 2A活性-现在与tau蛋白病和疾病进展有关。

 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.