Daily Abigail, Nath Avindra, Hersh Louis B
Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky 40538-0509, USA.
J Neurovirol. 2006 Jun;12(3):153-60. doi: 10.1080/13550280600760677.
Dementia associated with human immunodeficiency virus (HIV) infection occurs commonly in the aging population and amyloid depositions are noted in the brains of patients with HIV infection in younger age groups. This suggests a dysregulation of amyloid processing in the setting of HIV infection. The Tat protein of HIV has been implicated in the neuropathogenesis of HIV infection due to its neurotoxic and glial activation properties. However, Tat protein and Tat-derived peptides were recently also shown to inhibit neprilysin, the major amyloid beta peptide degrading enzyme in brain, in a cell aggregate system. This effect could contribute to the observed accumulation of amyloid in the brain of HIV-infected patients. The authors report here that peptides derived from the Tat protein, but not Tat protein itself, inhibit homogeneous recombinant neprilysin. This inhibition was found to be competitive and reversible and therefore does not involve covalent bond formation. Tat peptides and Tat protein were slowly hydrolyzed by neprilysin. Thus the accumulation of Tat-derived proteolytic fragments may serve to inhibit neprilysin and increase amyloid beta peptide levels.
与人类免疫缺陷病毒（HIV）感染相关的痴呆症常见于老年人群，而在较年轻年龄组的HIV感染患者大脑中也发现了淀粉样蛋白沉积。这表明在HIV感染情况下淀粉样蛋白加工出现失调。由于其神经毒性和神经胶质激活特性，HIV的Tat蛋白与HIV感染的神经发病机制有关。然而，最近在细胞聚集系统中还发现，Tat蛋白和源自Tat的肽能抑制脑内主要的淀粉样β肽降解酶——中性内肽酶。这种作用可能导致在HIV感染患者大脑中观察到的淀粉样蛋白积累。作者在此报告，源自Tat蛋白的肽而非Tat蛋白本身能抑制纯合重组中性内肽酶。发现这种抑制是竞争性和可逆的，因此不涉及共价键形成。Tat肽和Tat蛋白被中性内肽酶缓慢水解。因此，源自Tat的蛋白水解片段的积累可能会抑制中性内肽酶并增加淀粉样β肽水平。
