Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
Department of Medicine, University of California San Diego, La Jolla, CA, USA.
Neurobiol Dis. 2019 Oct;130:104502. doi: 10.1016/j.nbd.2019.104502. Epub 2019 Jun 22.
The neuropathogenesis of HIV associated neurocognitive disorders (HAND) involves disruption of mitochondrial homeostasis and increased neuroinflammation. However, it is unknown if alterations in mitochondrial biogenesis in the brain underlie the neuropathogenesis of HAND. In this study, neuropathological and molecular analyses of mitochondrial biogenesis and inflammatory pathways were performed in brain specimens from a well-characterized cohort of HIV+ cases that were on antiretroviral regimens. In vitro investigations using primary human astroglia and neurons were used to probe the underlying mechanisms of mitochondrial alterations. In frontal cortices from HAND brains compared to cognitive normal brains, total levels of transcription factors that regulate mitochondrial biogenesis, peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) and transcription factor A, mitochondrial (TFAM) were decreased. Immunohistochemical analyses revealed that TFAM was decreased in neurons and increased in astroglia. These changes were accompanied by decreased total mitochondrial DNA per cell and increased levels of messenger RNA for the proinflammatory cytokine interleukin (IL)-1β. To determine how IL-1β affects astroglial bioenergetic processes and mitochondrial activity, human astroglial cultures were exposed to recombinant IL-1β. IL-1β induced mitochondrial activity within 30 min of treatment, altered mitochondrial related gene expression, altered mitochondrial morphology, enhanced adenoside triphosphate (ATP) utilization and increased the expression of inflammatory cytokines. WIN55,212-2 (WIN), an aminoalkylindole derivative and cannabinoid receptor agonist, blocked IL-1β-induced bioenergetic fluctuations and inflammatory gene expression in astroglia independent of cannabinoid receptor (CB)1 and peroxisome proliferator-activated receptor (PPAR) γ. A PPARα antagonist reversed the anti-inflammatory effects of WIN in human astroglia. These results show that mitochondrial biogenesis is differentially regulated in neurons and astroglia in HAND brains and that targeting astroglial bioenergetic processes may be a strategy to modulate neuroinflammation.
HIV 相关神经认知障碍 (HAND) 的神经发病机制涉及线粒体动态平衡的破坏和神经炎症的增加。然而，尚不清楚大脑中线粒体生物发生的改变是否是 HAND 神经发病机制的基础。在这项研究中，对接受抗逆转录病毒治疗方案的 HIV 阳性病例的大脑标本进行了线粒体生物发生和炎症途径的神经病理学和分子分析。使用原代人星形胶质细胞和神经元进行的体外研究用于探究线粒体改变的潜在机制。与认知正常大脑相比，HAND 大脑的额皮质中线粒体生物发生的调节转录因子，过氧化物酶体增殖物激活受体 γ 共激活因子 1-α（PGC-1α）和转录因子 A，线粒体（TFAM）的总水平降低。免疫组织化学分析显示 TFAM 在神经元中减少，在星形胶质细胞中增加。这些变化伴随着每个细胞中线粒体 DNA 总量减少和促炎细胞因子白细胞介素（IL）-1β的信使 RNA 水平增加。为了确定 IL-1β如何影响星形胶质细胞的生物能过程和线粒体活性，将人星形胶质细胞培养物暴露于重组 IL-1β。IL-1β在治疗后 30 分钟内诱导线粒体活性，改变线粒体相关基因表达，改变线粒体形态，增强三磷酸腺苷（ATP）利用并增加炎症细胞因子的表达。WIN55,212-2（WIN），一种氨基烷基吲哚衍生物和大麻素受体激动剂，独立于大麻素受体（CB）1 和过氧化物酶体增殖物激活受体（PPAR）γ，阻断 IL-1β诱导的星形胶质细胞生物能波动和炎症基因表达。PPARα 拮抗剂逆转了 WIN 在人星形胶质细胞中的抗炎作用。这些结果表明，HAND 大脑中的神经元和星形胶质细胞中线粒体生物发生的调节存在差异，靶向星形胶质细胞的生物能过程可能是调节神经炎症的一种策略。
