Department of Psychology, University of South Carolina, Columbia, SC 29208, USA.
Institute of NeuroImmune Pharmacology, Seton Hall University, South Orange, NJ 07079, USA.
Viruses. 2022 Jun 10;14(6):1268. doi: 10.3390/v14061268.
The prevalence of HIV-1 associated neurocognitive disorders (HAND) is significantly greater in older, relative to younger, HIV-1 seropositive individuals; the neural pathogenesis of HAND in older HIV-1 seropositive individuals, however, remains elusive. To address this knowledge gap, abnormal protein aggregates (i.e., β-amyloid) were investigated in the brains of aging (>12 months of age) HIV-1 transgenic (Tg) rats. In aging HIV-1 Tg rats, double immunohistochemistry staining revealed abnormal intraneuronal β-amyloid accumulation in the prefrontal cortex (PFC) and hippocampus, relative to F344/N control rats. Notably, in HIV-1 Tg animals, increased β-amyloid accumulation occurred in the absence of any genotypic changes in amyloid precursor protein (APP). Furthermore, no clear amyloid plaque deposition was observed in HIV-1 Tg animals. Critically, β-amyloid was co-localized with neurons in the cortex and hippocampus, supporting a potential mechanism underlying synaptic dysfunction in the HIV-1 Tg rat. Consistent with these neuropathological findings, HIV-1 Tg rats exhibited prominent alterations in the progression of temporal processing relative to control animals; temporal processing relies, at least in part, on the integrity of the PFC and hippocampus. In addition, in post-mortem HIV-1 seropositive individuals with HAND, intraneuronal β-amyloid accumulation was observed in the dorsolateral PFC and hippocampal dentate gyrus. Consistent with observations in the HIV-1 Tg rat, no amyloid plaques were found in these post-mortem HIV-1 seropositive individuals with HAND. Collectively, intraneuronal β-amyloid aggregation observed in the PFC and hippocampus of HIV-1 Tg rats supports a potential factor underlying HIV-1 associated synaptodendritic damage. Further, the HIV-1 Tg rat provides a biological system to model HAND in older HIV-1 seropositive individuals.
HIV-1 相关神经认知障碍（HAND）的流行率在年长的 HIV-1 血清阳性个体中明显高于年轻个体；然而，年长的 HIV-1 血清阳性个体中 HAND 的神经发病机制仍然难以捉摸。为了解决这一知识空白，研究人员在衰老（>12 个月大）HIV-1 转基因（Tg）大鼠的大脑中研究了异常蛋白聚集体（即β-淀粉样蛋白）。在衰老的 HIV-1 Tg 大鼠中，双免疫组织化学染色显示前额叶皮层（PFC）和海马体中异常的神经元内β-淀粉样蛋白积累，与 F344/N 对照大鼠相比。值得注意的是，在 HIV-1 Tg 动物中，β-淀粉样蛋白的积累增加而没有淀粉样前体蛋白（APP）的任何基因型变化。此外，在 HIV-1 Tg 动物中没有观察到明显的淀粉样斑块沉积。关键的是，β-淀粉样蛋白与皮质和海马体中的神经元共定位，支持 HIV-1 Tg 大鼠突触功能障碍的潜在机制。与这些神经病理学发现一致，HIV-1 Tg 大鼠在时间处理的进展中表现出明显的改变，与对照动物相比；时间处理至少部分依赖于 PFC 和海马体的完整性。此外，在 HAND 的 HIV-1 血清阳性个体的尸检中，在背外侧 PFC 和海马齿状回中观察到神经元内β-淀粉样蛋白积累。与 HIV-1 Tg 大鼠的观察结果一致，在这些 HAND 的 HIV-1 血清阳性个体中没有发现淀粉样斑块。总之，在 HIV-1 Tg 大鼠的 PFC 和海马体中观察到的神经元内β-淀粉样蛋白聚集支持 HIV-1 相关突触 - 树突损伤的潜在因素。此外，HIV-1 Tg 大鼠提供了一个生物系统来模拟年长的 HIV-1 血清阳性个体中的 HAND。
