The Role of HIV-1 Tat in Alzheimer's Disease

描述（由申请人提供）：本申请的长期目标是在旨在建模/治疗神经退行性疾病的实验室技术方面对申请人进行培训。这些工作将在未来用于解决现有的医疗保健问题：缺乏目前的药物或治疗艾滋病毒相关痴呆症（HAD）的患者;神经精神疾病，已成为一种慢性疾病，这在很大程度上是由于高活性抗逆转录病毒治疗（HAART）延长患者的寿命。以毒性A β/β-淀粉样蛋白脑沉积形式的阿尔茨海默病（AD）样病理是HAD的共同特征，并且过去的工作以及我们的初步数据表明HIV-1达特抑制小胶质细胞吞噬A β肽的直接作用。事实上，据预测，在未来将有大量的艾滋病毒感染患者合并AD。为了研究慢性HAD样脑达特分泌对淀粉样β形成的影响，已经开发了以下具体目标。具体目标（1）的重点是建立一种新的具有AD样特征的HAD小鼠模型。考虑到HIV-1达特抑制小胶质细胞对A β的摄取（IFN-γ增强的过程）和HIV感染人群中淀粉样蛋白脑沉积的高患病率，我们建议交叉两种先前验证的AD（PSAPP小鼠）和HAD（GT-tg小鼠）小鼠模型。PSAPP小鼠产生AD样A| 3沉积物和相关炎症，而GT-tg小鼠表现出慢性脑HIV-1达特表达。我们假设这种慢性HIV-1达特分泌将导致PSAPP/GT-tg小鼠脑实质中A β/β-淀粉样蛋白沉积的早期发作和水平增加，与PSAPP小鼠和同窝对照相比。在行为测试之后，通过荧光显微镜以及蛋白质印迹分析定量脑中的AJ 31 -40和AJ 31- 42种类。用刚果红检测致密淀粉样蛋白沉积物。还将对凋亡神经元、突触密度、神经元计数、海马神经元的形态测定分析和炎症标志物进行定量。目的（2）在GT-tg/PSAPP小鼠模型中测试EGCG作为体内干预的效果。我们计划在预防和治疗范例中，通过腹腔内给予EGGG，在体内验证EGCG治疗是否可以对抗达特对PSAPP/GT-tg小鼠中上述终点的作用。假设EGCG将在PSAPP/GT-tg小鼠中赋予上述病理终点的显著减弱。

DESCRIPTION (provided by applicant): This applications broad-long term objectives are to train in the applicant in laboratory techniques aimed at modeling/treating neurodegenerative disease. These works will be used in the future to solve an existing health care problem: the lack of current prophylactics or treatments for patients who have HIV-associated dementia (HAD); a neuropsychiatric disorder which has become a chronic disease due in large part to extension of patient life spans by highly active anti-retroviral therapy (HAART). Alzheimer's disease (AD) - like pathology in the form of toxic A(3/(3-amyloid brain deposition is a common feature of HAD, and past works as well as our preliminary data indicate a direct role for HIV-1 Tat inhibition of microglial phagocytosis of Ap peptide. Indeed it is predicted that in the future there will be a large population of HIV infected patients with comorbid AD. To study the effects of chronic HAD-like brain Tat secretion on amyloid beta formation, the following specific aims have been developed. Specific Aim (1) focuses on the creation of a novel mouse model of HAD with AD-like features. Given that HIV-1 Tat inhibits microglial uptake of A(3 (a process augmented by IFN-gamma) and the high prevalence of amyloid brain deposition in the HIV infected population, we propose to cross two previously validated AD (PSAPP mice) and HAD (GT-tg mice) mouse models. PSAPP mice develop AD-like A|3 deposits and associated inflammation while GT-tg mice demonstrate chronic brain HIV-1 Tat expression. We hypothesize this chronic HIV-1 Tat secretion will cause an early onset and increased level of A(3/(3-amyloid deposits in the brain parenchyma of PSAPP/GT-tg mice compared to PSAPP mice and littermate controls. Following behavioral testing, the AJ31-40 and A(31- 42 species will quantified in brain via fluorescence microscopy as well as western blot analysis. Compact amyloid deposits will be detected with Congo red. Apoptotic neurons, synaptic density, neuron counting, morphometric analysis of hippocampal neurons, and inflammatory markers will be quantified as well. Aim (2) tests EGCG as an intervention in vivo in the GT-tg/PSAPP mouse model. We plan to validate in vivo whether EGCG treatment can oppose Tat's effect on the above endpoints in PSAPP/GT-tg mice by intraperitoneally administering EGGG, in prophylactic and therapeutic paradigms. It is hypothesized that EGCG will confer a marked attenuation of the above described pathological end-points in PSAPP/GT-tg mice.