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对申请人进行旨在模拟/治疗神经退行性疾病的实验室技术方面的培训。这些工作将在未来用于解决现有的医疗保健问题：艾滋病毒相关痴呆症(HAD)患者目前缺乏预防或治疗；神经精神障碍，其已成为一种慢性病，很大程度上是由于高效抗逆转录病毒疗法(HAART)延长了患者的生命。阿尔茨海默病(AD)样病理形式的毒性A(3/(3)淀粉样脑沉积是HAD的一个共同特征，过去的工作以及我们的初步数据表明，HIV-1 TAT直接作用于抑制AP肽的小胶质细胞吞噬。事实上，据预测，未来将有大量艾滋病毒感染的患者患有阿尔茨海默病。为了研究慢性HAD样脑TAT分泌对淀粉样β蛋白形成的影响，已经制定了以下特定的目标。具体目标(1)致力于建立一种具有AD样特征的新型HAD小鼠模型。鉴于HIV-1Tat抑制小胶质细胞对A(3)的摄取(这一过程被干扰素-γ增强)和在HIV感染人群中淀粉样脑沉积的高流行率，我们建议交叉建立两个先前验证的AD(PSAPP小鼠)和HAD(GT-TG小鼠)小鼠模型。PSAPP小鼠出现AD样A|3沉积和相关炎症，而GT-TG小鼠表现出慢性脑部HIV-1Tat表达。我们推测，这种慢性的HIV-1 Tat分泌将导致PSAPP/GT-TG小鼠脑实质中A(3/(3)-淀粉样蛋白沉积比PSAPP小鼠和小鼠对照组更早和更高水平。在行为测试之后，AJ31-40和A(31-42种)将通过荧光显微镜和蛋白质印迹分析在大脑中进行定量。刚果红将检测到致密的淀粉样沉积物。此外，还将对凋亡神经元、突触密度、神经元计数、海马神经元形态计量学分析和炎症标志物进行量化。目的(2)在GT-TG/PSAPP小鼠模型中检测EGCG的体内干预作用。我们计划通过预防和治疗方案，在体内验证EGCG治疗是否可以通过腹腔注射EGGG来对抗TAT对PSAPP/GT-TG小鼠上述终点的影响。假设EGCG将显着减弱PSAPP/GT-TG小鼠的上述病理终点。

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.