Merali Salim, Barrero Carlos A, Sacktor Ned C, Haughey Norman J, Datta Prasun K, Langford Dianne, Khalili Kamel
Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, Pennsylvania, USA.
Department of Neurology, Johns Hopkins Memory and Alzheimer's Disease Treatment Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
J AIDS Clin Res. 2014;5(6):1000312. doi: 10.4172/2155-6113.1000312.
Spermidine/spermine-N-acetytransferase (SSAT) is the key enzyme in the catabolism of polyamines that are involved in regulating NMDA functioning. Over expression of SSAT leads to abnormal metabolic cycling and may disrupt NMDA receptor signaling. In fact, the HIV protein Tat induces neurotoxicity involving polyamine/NMDA receptor interactions. Thus, we investigated abnormal polyamine cycling in HIV+ participants with varying degrees of HIV-associated neurocognitive disorders.
Acetyl-polyamine (SSAT products) levels were assessed by HPLC in CSF from 99 HIV-infected participants (no cognitive impairment (NCI, n=25), asymptomatic neurocognitive impairment (ANI, n=25), mild cognitive and motor disorders (MCMD, n=24), and HIV-associated dementia (HAD, n=25)). Polyamine levels in brain tissues from a subset of participants (uninfected (n=3), NCI (n=3), and MNCD (n=3)) were also assessed. Human primary astrocytes expressing HIV Tat were assessed for levels of the SSAT activity.
Activation of the polyamine catabolic enzyme, SSAT increases polyamine flux in brain and CSF of HIV infected individuals with HIV-associated neurocognitive disorders. CSF levels of acetylated polyamine increase with the degree of HAND severity as indicated by significantly increased acetylpolyamine levels in HAD participants compared to NCI and ANI (p<0.0001) and between MCMD and NCI and ANI (p<0.0001). studies suggest that the HIV protein Tat may be responsible in part for astrocyte-derived acetyl polyamine release.
Our data suggest that polyamine metabolism may play a pivotal role in the neurodegeneration process among HAND patients. Changes in polyamine flux may serve as a potential predictive diagnostic biomarker for different severities of HAND.
亚精胺/精胺-N-乙酰转移酶（SSAT）是多胺分解代谢中的关键酶，多胺参与调节N-甲基-D-天冬氨酸（NMDA）功能。SSAT的过度表达会导致异常的代谢循环，并可能破坏NMDA受体信号传导。事实上，人类免疫缺陷病毒（HIV）蛋白Tat会诱导涉及多胺/NMDA受体相互作用的神经毒性。因此，我们研究了不同程度的HIV相关神经认知障碍的HIV阳性参与者中异常的多胺循环。
通过高效液相色谱法（HPLC）评估了99名HIV感染参与者（无认知障碍（NCI，n = 25）、无症状神经认知障碍（ANI，n = 25）、轻度认知和运动障碍（MCMD，n = 24）以及HIV相关痴呆（HAD，n = 25））脑脊液中的乙酰化多胺（SSAT产物）水平。还评估了一部分参与者（未感染（n = 3）、NCI（n = 3）和MNCD（n = 3））脑组织中的多胺水平。对表达HIV Tat的人原代星形胶质细胞的SSAT活性水平进行了评估。
在患有HIV相关神经认知障碍的HIV感染个体的大脑和脑脊液中，多胺分解代谢酶SSAT的激活会增加多胺通量。乙酰化多胺的脑脊液水平随着HIV相关神经认知障碍（HAND）严重程度的增加而升高，HAD参与者的乙酰化多胺水平相比NCI和ANI显著升高（p < 0.0001），MCMD与NCI和ANI之间也显著升高（p < 0.0001）。研究表明，HIV蛋白Tat可能部分导致星形胶质细胞衍生的乙酰化多胺释放。
我们的数据表明，多胺代谢可能在HAND患者的神经退行性变过程中起关键作用。多胺通量的变化可能作为不同严重程度HAND的潜在预测性诊断生物标志物。
