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

描述（由申请人提供）：该申请的长期目标是培训申请人在模拟/治疗神经退行性疾病的实验室技术。这些工作将在未来用于解决现有的卫生保健问题：目前缺乏针对艾滋病毒相关痴呆（HAD）患者的预防措施或治疗方法；这是一种神经精神疾病，在很大程度上由于高效抗逆转录病毒疗法（HAART）延长了患者的寿命而成为一种慢性疾病。阿尔茨海默病（AD）样病理以毒性A(3/(3)淀粉样蛋白脑沉积的形式出现是AD的共同特征，过去的研究和我们的初步数据表明HIV-1 Tat直接作用于抑制Ap肽的小胶质吞噬。事实上，据预测，在未来将会有大量的HIV感染患者合并AD。为了研究慢性had样脑Tat分泌对β淀粉样蛋白形成的影响，我们制定了以下具体目标。具体目标(1)侧重于创建具有广告样特征的新型HAD小鼠模型。鉴于HIV-1 Tat抑制小胶质细胞对A(3的摄取（一个由ifn - γ增强的过程）以及在HIV感染人群中淀粉样蛋白脑沉积的高患病率，我们建议交叉两个先前验证的AD （papp小鼠）和HAD （GT-tg小鼠）小鼠模型。papp小鼠出现ad样A bbb3沉积和相关炎症，而GT-tg小鼠表现出慢性脑HIV-1 Tat表达。我们假设这种慢性HIV-1 Tat分泌会导致papp /GT-tg小鼠的脑实质中A(3/(3)淀粉样蛋白沉积水平比papp小鼠和同鼠对照组早发病和增加。行为学测试后，采用荧光显微镜和western blot方法对AJ31-40和A（31- 42）进行脑内定量分析。刚果红可以检测到致密的淀粉样蛋白沉积。凋亡神经元、突触密度、神经元计数、海马神经元形态学分析和炎症标志物也将被量化。目的(2)在GT-tg/ papp小鼠模型中测试EGCG在体内的干预作用。我们计划在papp /GT-tg小鼠中通过腹腔注射EGCG，在预防和治疗两种模式下验证EGCG治疗是否可以对抗Tat对上述终点的影响。据推测，EGCG将赋予papp /GT-tg小鼠上述病理终点的显著衰减。

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.