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

描述（由申请人提供）：HIV-1流行病学的一个新因素是感染HIV-1的老年人口增加。这一现象引起了严重关注，因为年龄的增加可能对他们的认知功能产生不利影响，并促进和增强艾滋病毒感染患者神经退行性疾病的发展。本申请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蛋白β（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。由于血液传播的A2是淀粉样蛋白沉积在大脑中的主要来源，我们形成了本提案的中心假设，即HIV-1诱导的脑内皮细胞中转运蛋白活性的特异性改变导致细胞内A2积累及其跨内皮通道。我们发现，HIV-1诱导的晚期糖基化终末产物（AGEs）受体的活性和ABC外排转运蛋白（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称为小窝的特定子集相关。此外，这些转运蛋白的表达似乎是由小GTP酶，如Ras和Rho途径，也定位于脂筏/小窝调节。因此，我们建议，功能性脂筏和小窝提供的信号平台，是有害的HIV-1诱导的血管机制，导致A2在中枢神经系统中的积累。 从我们的建议所产生的数据将是至关重要的，更好地了解HIV-1相关的脑血管损伤的分子机制，在老年HIV-1感染者。拟议研究产生的结果也可能与其他具有显著脑血管成分并与淀粉样蛋白积累相关的神经退行性疾病有关，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.