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

 描述(申请人提供)：基因、环境和性别影响阿尔茨海默病(AD)的风险，但研究年龄、ApoE4、高脂肪和性别等常见风险因素的模型开发及其相互作用令人惊讶地有限。Tau是主要的缠结蛋白，可以位于神经炎斑块的主要成分β-淀粉样蛋白(Aβ)的下游，但tau可以独立于Aβ而积累，以响应包括神经炎症在内的其他因素。高饱和脂肪的西方饮食是AD的危险因素，它增加神经炎症和tau的表达，与Aβ沉积无关。高饱和脂肪饮食增加了人类载脂蛋白E4的风险和JNK上游脂筏中src/fyn激酶的激活，而这与饮食中的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失活、pJNK和ptau。对人类载脂蛋白E4数据的综合基因组分析显示，在E4网络枢纽的中心，FYN激酶增加。虽然E4可以调节Aβ的沉积，但女性E4携带者的风险要高得多，最近AD神经成像倡议的数据也证实了这一点，这也发现女性E4携带者有更多的脑脊液tau，而与Aβ无关。这表明E4/性别/tau的交互作用导致了E4性别风险。然而，目前还没有相互作用的模型来测试性别风险机制或涉及E4和tau的治疗和相互作用。在突变型脊椎病模型中引入ApoEKO背景可以增加ptau阳性神经突起的数量，这表明ApoE功能的丧失加速了脊椎病。在目标1中，我们将HutauTg小鼠与ApoE KO背景杂交(EKO-TAU)，以确定对tau发病的影响，性别和性腺切除的影响，以仿效性腺类固醇随年龄的丧失。在目标2中，我们将人类TRApoE3或ApoE4杂交到这条EKO-TAU系中，以生成E3TAU和E4TAU模型，为探索独立于(或依赖于)Aβ的tau-ApoE亚型关联创造资源。这一目的将确定ApoE在tau发病机制中的性别和高脂肪的调节和交互作用。由于我们的初步数据支持饱和脂肪/src/fyn/Pp2A/jnk和Akt/Gsk3途径的作用和性别效应，Aim 3使用一个纯粹的自体病模型来确定西方饮食(17%脂肪)和性别及其交互作用在tau发病机制、神经炎症、src/fyn、RACK1和PP2A以及AKT/Gsk3调节中的作用，并且不依赖于Aβ。我们将评估突触和认知缺陷，包括FYN在内的tau激酶活性的变化，神经炎症和我们的焦点，PP2A的失调。这些目标的完成将具有广泛的意义，包括开发一个新的ApoE-tau相互作用模型，展示tau积累、激酶调节和神经炎症的异构体差异，以及高脂诱导的tau病的ApoE x性别特异性。新的模型将允许测试针对ApoE依赖的tau效应的新疗法。这一影响很大，因为有令人信服的数据表明，AD和ApoE4都调节PP2A活性--现在与直肠曲张和疾病进展有关。

 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.