PDF(Pubmed)
Abstract：
Our previous findings demonstrated that astrocytic HIF-1α plays a major role in HIV-1 Tat-mediated amyloidosis which can lead to Alzheimer\'s-like pathology-a comorbidity of HIV-Associated Neurocognitive Disorders (HAND). These amyloids can be shuttled in extracellular vesicles, and we sought to assess whether HIV-1 Tat stimulated astrocyte-derived EVs (ADEVs) containing the toxic amyloids could result in neuronal injury in vitro and in vivo. We thus hypothesized that blocking HIF-1α could likely mitigate HIV-1 Tat-ADEV-mediated neuronal injury. Rat hippocampal neurons when exposed to HIV-1 Tat-ADEVs carrying the toxic amyloids exhibited amyloid accumulation and synaptodendritic injury, leading to functional loss as evidenced by alterations in miniature excitatory post synaptic currents. The silencing of astrocytic HIF-1α not only reduced the biogenesis of ADEVs, as well as amyloid cargos, but also ameliorated neuronal synaptodegeneration. Next, we determined the effect of HIV-1 Tat-ADEVs carrying amyloids in the hippocampus of naive mice brains. Naive mice receiving the HIV-1 Tat-ADEVs, exhibited behavioural changes, and Alzheimer\'s \'s-like pathology accompanied by synaptodegeneration. This impairment(s) was not observed in mice injected with HIF-1α silenced ADEVs. This is the first report demonstrating the role of amyloid-carrying ADEVs in mediating synaptodegeneration leading to behavioural changes associated with HAND and highlights the protective role of HIF-1α.
摘要：
我们先前的发现表明，星形胶质细胞HIF-1α在HIV-1Tat介导的淀粉样变性中起着重要作用，这种淀粉样变性可导致阿尔茨海默病-HIV相关神经认知障碍（HAND）的合并症。这些淀粉样蛋白可以在细胞外囊泡中穿梭，我们试图评估HIV-1Tat刺激的含有毒性淀粉样蛋白的星形胶质细胞衍生的EV（ADEV）是否会在体外和体内导致神经元损伤。因此，我们假设阻断HIF-1α可能减轻HIV-1Tat-ADEV介导的神经元损伤。当暴露于携带有毒淀粉样蛋白的HIV-1Tat-ADEVs时，大鼠海马神经元表现出淀粉样蛋白积累和突触树突状损伤，导致功能丧失，如微型兴奋性突触后电流的改变所证明。星形胶质细胞HIF-1α的沉默不仅降低了ADEVs的生物发生,以及淀粉样蛋白货物，而且还改善了神经元突触变性.接下来,我们确定了携带淀粉样蛋白的HIV-1Tat-ADEV在幼稚小鼠大脑海马中的作用。接受HIV-1Tat-ADEVs的幼稚小鼠，表现出行为变化，和伴有突触变性的阿尔茨海默氏症样病理。在注射HIF-1α沉默ADEV的小鼠中未观察到这种损伤。这是第一份报告，证明了携带淀粉样蛋白的ADEVs在介导突触变性中的作用，导致与HAND相关的行为变化，并强调了HIF-1α的保护作用。
