HIV-1 and amyloid beta interactions at the blood-brain barrier

描述(申请人提供)：艾滋病毒-1流行病学的一个新因素是感染艾滋病毒-1的老年人口增加。这一现象非常令人担忧，因为年龄的增加可能会对他们的认知功能产生不利影响，并促进和促进艾滋病毒感染患者神经退行性疾病的发展。目前的应用是基于我们最近的观察，即暴露于HIV-1导致人脑微血管内皮细胞中淀粉样β蛋白(A2)水平显著增加。这些发现与强有力的临床证据一致，表明HIV-1感染患者大脑中淀粉样蛋白沉积增加。由于血液中的A2是脑内淀粉样蛋白沉积的主要来源，我们形成了本假设的中心假说，即HIV-1诱导的脑内皮细胞转运蛋白活性的特异性改变导致A2在细胞内聚集并通过内皮。我们发现HIV-1诱导的晚期糖基化终末产物受体(RAGE)活性和ABC外排转运体(即P-糖蛋白[PGP]和乳腺癌耐药蛋白[BCRP])的改变可能参与了这些过程。值得注意的是，这些转运蛋白与细胞膜脂筏或其特定的称为小窝的亚群有关。此外，这些转运蛋白的表达似乎受到小的GTP酶的调节，例如Ras和Rho通路，它们也定位于脂筏/小窝中。因此，我们认为功能性脂筏和小窝为HIV-1诱导的导致A2在中枢神经系统积聚的血管机制提供了不利的信号平台。 我们建议的数据对于更好地理解老年HIV-1感染者与HIV-1相关的脑血管损伤的分子机制至关重要。拟议中的研究产生的结果也可能与其他神经退行性疾病相关，这些疾病具有重要的脑血管成分，并与淀粉样蛋白堆积有关，如阿尔茨海默病。

DESCRIPTION (provided by applicant): A new element of HIV-1 epidemiology is an increase in the older population infected with HIV-1. This phenomenon is of significant concern because the increasing age may have a detrimental effect on their cognitive functions and facilitate and enhance the development of neurodegenerative diseases in HIV-infected patients. The present application is based on our recent observations that exposure to HIV-1 results in a significant increase in amyloid beta (A2) levels in human brain microvascular endothelial cells. These findings are consistent with strong clinical evidence that indicates increased amyloid deposition in the brain of HIV-1-infected patients. Because blood-borne A2 is the main source of amyloid deposition in the brain, we formed the central hypothesis of the present proposal that HIV-1-induced specific alterations of transporter activities in brain endothelial cells results in intracellular A2 accumulation and its transendothelial passage. We identified that HIV-1-induced activity of the receptor for advanced glycation end products (RAGE) and alterations of ABC efflux transporters (namely, P-glycoprotein [Pgp] and breast cancer resistance protein [BCRP]), may be involved in these processes. It is striking to note that these transporters are associated with cell membrane lipid rafts or their specific subset called caveolae. In addition, expression of these transporters appears to be regulated by small GTPases, such as the Ras and Rho pathways, that are also localized in lipid rafts/caveolae. Therefore, we propose that functional lipid rafts and caveolae provide the signaling platform that is detrimental for HIV-1-induced vascular mechanisms leading to A2 accumulation in the CNS. Data arising from our proposal will be critical for a better understanding of the molecular mechanisms underlying HIV-1-related cerebrovascular injury in older HIV-1-infected individuals. The results generated by the proposed research are also likely to be relevant to other neurodegenerative diseases that have significant cerebrovascular components and are associated with amyloid accumulation, such as Alzheimer's disease.