Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, United States of America.
Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, United States of America; The Edward Via College of Osteopathic Medicine, Spartanburg, SC 29303, United States of America.
Exp Neurol. 2021 Jan;335:113489. doi: 10.1016/j.expneurol.2020.113489. Epub 2020 Sep 29.
The persistence of HIV in the central nervous system leads to cognitive deficits in up to 50% of people living with HIV even with systemic suppression by antiretroviral treatment. The interaction of chronic inflammation with age-associated degeneration places these individuals at increased risk of accelerated aging and other neurodegenerative diseases and no treatments are available that effectively halt these processes. The adverse effects of aging and inflammation may be mediated, in part, by an increase in the expression of the p75 neurotrophin receptor (p75) which shifts the balance of neurotrophin signaling toward less protective pathways. To determine if modulation of p75 could modify the disease process, we treated HIV gp120 transgenic mice with a small molecule ligand designed to engage p75 and downregulate degenerative signaling. Daily treatment with 50 mg/kg LM11A-31 for 4 months suppressed age- and genotype-dependent activation of microglia, increased microtubule associated protein-2 (MAP-2), reduced dendritic varicosities and slowed the loss of parvalbumin immunoreactive neurons in the hippocampus. An age related accumulation of microtubule associated protein Tau was identified in the hippocampus in extracellular clusters that co-expressed p75 suggesting a link between Tau and p75. Although the significance of the relationship between p75 and Tau is unclear, a decrease in Tau-1 immunoreactivity as gp120 mice entered old age (>16 months) suggests that the Tau may transition to more pathological modifications; a process blocked by LM11A-31. Overall, the effects of LM11A-31 are consistent with strong neuroprotective and anti-inflammatory actions that have significant therapeutic potential.
HIV 持续存在于中枢神经系统中，导致高达 50%的 HIV 感染者出现认知缺陷，即使通过抗逆转录病毒治疗实现了全身抑制。慢性炎症与年龄相关的退行性变相互作用，使这些个体面临加速衰老和其他神经退行性疾病的风险增加，而目前尚无有效的治疗方法可以阻止这些过程。衰老和炎症的不良影响可能部分通过增加 p75 神经营养素受体（p75）的表达来介导，这会使神经营养素信号向保护作用较小的途径倾斜。为了确定调节 p75 是否可以改变疾病进程，我们用一种小分子配体治疗 HIV gp120 转基因小鼠，该配体旨在与 p75 结合并下调退行性信号。用 50mg/kg LM11A-31 每天治疗 4 个月，可抑制小胶质细胞的年龄和基因型依赖性激活，增加微管相关蛋白-2（MAP-2），减少树突棘和减缓海马区钙蛋白免疫反应性神经元的丢失。在海马体中发现了与 p75 共表达的微管相关蛋白 Tau 的年龄相关积累，这表明 Tau 与 p75 之间存在联系。尽管 p75 和 Tau 之间的关系意义尚不清楚，但在 gp120 小鼠进入老年（>16 个月）时，Tau-1 免疫反应性降低表明 Tau 可能向更具病理改变的形式转化；这一过程被 LM11A-31 阻断。总体而言，LM11A-31 的作用与强大的神经保护和抗炎作用一致，具有显著的治疗潜力。
