HIV-1 TAT inhibits microglial phagocytosis of Abeta peptide.
HIV-1 TAT inhibits microglial phagocytosis of Abeta peptide.
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发表时间：
2008
影响因子：
1.4
通讯作者：
B. Giunta;Yuyan Zhou;Huayan Hou;Elona Rrapo;Francisco Fernandez;Jun Tan
中科院分区：
文献类型：
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作者：
B. Giunta;Yuyan Zhou;Huayan Hou;Elona Rrapo;Francisco Fernandez;Jun Tan
人类免疫缺陷病毒（HIV）相关痴呆（HAD）是一种皮层下神经精神综合征，在高活性抗逆转录病毒治疗（HAART）时代患病率增加。几项研究表明，艾滋病毒患者的大脑淀粉样变性增加，并表明未来可能会有相当数量的长期艾滋病毒幸存者合并阿尔茨海默病（AD）。我们发现HIV-1 Tat蛋白抑制小胶质细胞对Abeta1-42肽的摄取，这一过程被干扰素- γ (ifn - γ)增强，并被STAT1抑制剂(-)-表没食子儿茶素-3-没食子酸酯（EGCG）拯救。据推测，减少β摄取是通过ifn - γ介导的STAT1激活发生的。这个过程通过II类反激活因子（CIITA）的激活，促进小胶质细胞从吞噬表型向抗原呈递表型的转换。此外，我们发现HIV-1 Tat显著破坏载脂蛋白3 (Apo-E3)，促进小胶质细胞摄取β。由于Tat已被证明与低密度脂蛋白（LRP）受体直接相互作用，从而抑制其配体（包括载脂蛋白E4 （Apo-E4）和Abeta肽）在神经元中的摄取，我们进一步假设LRP的类似抑制可能发生在小胶质细胞中。未来的研究将需要充分表征ifn - γ增强HIV-1 Tats破坏小胶质细胞吞噬Abeta和Apo-E3的机制。
Human immunodeficiency virus (HIV)-associated dementia (HAD) is a subcortical neuropsychiatric syndrome that has increased in prevalence in the era of highly active antiretroviral therapy (HAART). Several studies demonstrated increased amyloidosis in brains of HIV patients and suggested that there may be a significant number of long-term HIV survivors with co-morbid Alzheimer's disease (AD) in the future. We show HIV-1 Tat protein inhibits microglial uptake of Abeta1-42 peptide, a process that is enhanced by interferon-gamma (IFN-gamma) and rescued by the STAT1 inhibitor (-)-epigallocatechin-3-gallate (EGCG). It is hypothesized that reduced Abeta uptake occurs through IFN-gamma mediated STAT1 activation. This process promotes a switch from a phagocytic to an antigen presenting phenotype in microglia through activation of class II transactivator (CIITA). Additionally, we show that HIV-1 Tat significantly disrupts apolipoprotein-3 (Apo-E3) promoted microglial Abeta uptake. As Tat has been shown to directly interact with the low density lipoprotein (LRP) receptor and thus inhibit the uptake of its ligands including apolipoprotein E4 (Apo-E4) and Abeta peptide in neurons, we further hypothesize that a similar inhibition of LRP may occur in microglia. Future studies will be required to fully characterize the mechanisms underlying IFN-gamma enhancement of HIV-1 Tats disruption of microglial phagocytosis of Abeta and Apo-E3.