PDF(Pubmed)
Abstract：
Over 38 million people worldwide are living with HIV/AIDS, and more than half of them are affected by HIV-associated neurocognitive disorders (HAND). Such disorders are characterized by chronic neuroinflammation, neurotoxicity, and central nervous system deterioration, which lead to short- or long-term memory loss, cognitive impairment, and motor skill deficits that may show gender disparities. However, the underlying mechanisms remain unclear. Our previous study suggested that HIV-1 infection and viral protein R (Vpr) upregulate the SUR1-TRPM4 channel associated with neuroinflammation, which may contribute to HAND. The present study aimed to explore this relationship in a mouse model of HAND. This study employed the HIV transgenic Tg26 mouse model, comparing Tg26 mice with wildtype mice in various cognitive behavioral and memory tests, including locomotor activity tests, recognition memory tests, and spatial learning and memory tests. The study found that Tg26 mice exhibited impaired cognitive skills and reduced learning abilities compared to wildtype mice, particularly in spatial memory. Interestingly, male Tg26 mice displayed significant differences in spatial memory losses (p < 0.001), while no significant differences were identified in female mice. Consistent with our early results, SUR1-TRPM4 channels were upregulated in Tg26 mice along with glial fibrillary acidic protein (GFAP) and aquaporin 4 (AQP4), consistent with reactive astrocytosis and neuroinflammation. Corresponding reductions in neurosynaptic responses, as indicated by downregulation of Synapsin-1 (SYN1) and Synaptophysin (SYP), suggested synaptopathy as a possible mechanism underlying cognitive and motor skill deficits. In conclusion, our study suggests a possible relationship between SUR1-TRPM4-mediated neuroinflammation and synaptopathy with impairments of learning and memory in mice with HAND. These findings could help to develop new therapeutic strategies for individuals living with HAND.
摘要：
全世界有超过3800万人感染艾滋病毒/艾滋病，其中一半以上受到HIV相关神经认知障碍（HAND）的影响。这些疾病的特征是慢性神经炎症，神经毒性，中枢神经系统恶化，导致短期或长期记忆丧失，认知障碍，以及可能显示性别差异的运动技能缺陷。然而,潜在机制尚不清楚.我们先前的研究表明，HIV-1感染和病毒蛋白R（Vpr）上调与神经炎症相关的SUR1-TRPM4通道，这可能有助于手。本研究旨在探索HAND小鼠模型中的这种关系。本研究采用HIV转基因Tg26小鼠模型，在各种认知行为和记忆测试中比较Tg26小鼠与野生型小鼠，包括运动活动测试，识别记忆测试，以及空间学习和记忆测试。研究发现，与野生型小鼠相比，Tg26小鼠表现出认知技能受损和学习能力下降，特别是在空间记忆中。有趣的是,雄性Tg26小鼠在空间记忆丧失方面表现出显著差异(p<0.001)，而在雌性小鼠中没有发现显着差异。与我们早期的结果一致，Tg26小鼠SUR1-TRPM4通道与胶质纤维酸性蛋白（GFAP）和水通道蛋白4（AQP4）一起上调，与反应性星形细胞增多和神经炎症一致。神经突触反应的相应减少，如突触素-1（SYN1）和突触素（SYP）的下调所示，提示突触病是认知和运动技能缺陷的潜在机制。总之,我们的研究提示,在HAND小鼠中,SUR1-TRPM4介导的神经炎症和突触病变可能与学习和记忆障碍相关.这些发现可能有助于为患有HAND的个体开发新的治疗策略。
