Giunta Brian, Hou Houyan, Zhu Yuyan, Rrapo Elona, Tian Jun, Takashi Mori, Commins Deborah, Singer Elyse, He Johnny, Fernandez Francisco, Tan Jun
Department of Psychiatry and Behavioral Medicine, Neuroimmunology Laboratory, University of South Florida College of Medicine Tampa, Florida 33613, USA.
Int J Clin Exp Pathol. 2009;2(5):433-43. Epub 2009 Jan 30.
Prevalence of HIV-associated cognitive impairment is rising. Amyloid-beta (A-beta) plaque deposition in the brain may be a contributing factor as epidemiological data suggests significant numbers of long-term HIV survivors are at elevated risk of developing Alzheimer's disease (AD). HIV-1 Tat-induced A-beta deposition, tau phosphorylation, and subsequent neuronal death could be risk factors for subsequent AD and/or HIV-related cognitive impairment. To mimic this clinical condition, we generated mice with HIV-1 Tat-induced AD-like pathology. We first performed a short-term Doxycycline (dox) dosing (54, 108, and 216 mg/kg/day) study in transgenic mice whose astrocytes express HIV-1 Tat via activation of a GFAP/dox-inducible promoter. After one week, mouse brains were examined histologically and the expression of Bcl-xL, Bax, and phospho-tau was investigated by Western blotting. We next cross-bred these mice with the PSAPP mouse model of AD. To simulate chronic Tat secretion over periods longer than one week, we used an optimized dose of 54 mg/kg/day on a biweekly basis over three months; based on the initial dose ranging study in the Tat transgenic mice. This was followed by antisera detection of A-beta, and Western blot for phospho-tau, Bcl-xL, and Bax. Tat significantly induced neuron degeneration and tau phosphorylation in Tat transgenic mice, dox dependently (P<0.001) with the most robust effects at the 216 mg/kg/day dose. In the long term study, similar effects at the chronic 54 mg/kg/day dose were observed in PSAPP/Tat mice induced with dox. These mice also showed significantly more A-beta deposition (P < 0.05), neurodegeneration, neuronal apoptotic signaling, and phospho-tau than PSAPP mice (P < 0.05). In conclusion, HIV-1 Tat significantly promotes AD-like pathology in PSAPP/Tat mice. This model may provide a framework in which to identify new mechanisms involved in cognitive impairment in the HIV infected population, and possible treatments. Additional works will be needed to fully characterize the mechanism(s) of HIV- induced amyloid deposition, and also to uncover viral mechanisms promoting AD-like pathology in general.
与HIV相关的认知障碍患病率正在上升。大脑中的β-淀粉样蛋白（A-beta）斑块沉积可能是一个促成因素，因为流行病学数据表明，大量长期存活的HIV感染者患阿尔茨海默病（AD）的风险升高。HIV-1反式激活转录激活因子（Tat）诱导的A-beta沉积、tau蛋白磷酸化以及随后的神经元死亡可能是后续发生AD和/或HIV相关认知障碍的危险因素。为了模拟这种临床情况，我们构建了具有HIV-1 Tat诱导的AD样病理特征的小鼠模型。我们首先对通过激活胶质纤维酸性蛋白（GFAP）/强力霉素（dox）诱导型启动子使星形胶质细胞表达HIV-1 Tat的转基因小鼠进行了短期强力霉素给药（54、108和216 mg/kg/天）研究。一周后，对小鼠大脑进行组织学检查，并通过蛋白质免疫印迹法研究Bcl-xL、Bax和磷酸化tau蛋白的表达。接下来，我们将这些小鼠与AD的PSAPP小鼠模型进行杂交。为了模拟超过一周时间的慢性Tat分泌，我们根据在Tat转基因小鼠中的初始剂量范围研究，以54 mg/kg/天的优化剂量每两周给药一次，持续三个月。随后进行A-beta的抗血清检测，以及磷酸化tau蛋白、Bcl-xL和Bax的蛋白质免疫印迹分析。Tat在Tat转基因小鼠中显著诱导神经元变性和tau蛋白磷酸化，呈强力霉素依赖性（P<0.001），在216 mg/kg/天剂量时效果最为显著。在长期研究中，在用强力霉素诱导的PSAPP/Tat小鼠中，观察到慢性54 mg/kg/天剂量具有类似的效果。这些小鼠还表现出比PSAPP小鼠显著更多的A-beta沉积（P < 0.05）、神经变性、神经元凋亡信号以及磷酸化tau蛋白（P < 0.05）。总之，HIV-1 Tat显著促进PSAPP/Tat小鼠中的AD样病理特征。该模型可能提供一个框架，用于识别HIV感染人群中认知障碍所涉及的新机制以及可能的治疗方法。还需要进一步的研究来全面表征HIV诱导淀粉样蛋白沉积的机制，以及揭示一般情况下促进AD样病理特征的病毒机制。
