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的老年人口的增加。这一现象令人极为关切，因为年龄的增长可能对他们的认知功能产生不利影响，并促进和加强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，暴露于HIV-1导致人脑微血管内皮细胞中β淀粉样蛋白（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。由于血源性A2是脑内淀粉样蛋白沉积的主要来源，我们形成了本研究的中心假设，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了细胞内A2的积累及其跨内皮通道。我们发现hiv -1诱导的晚期糖基化终产物受体（RAGE）的活性和ABC外排转运蛋白（即p糖蛋白[Pgp]和乳腺癌抵抗蛋白[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称为小泡的特定亚群有关。此外，这些转运体的表达似乎受到小gtpase的调节，如Ras和Rho途径，它们也位于脂筏/小泡中。因此，我们提出功能性脂筏和小泡为hiv -1诱导的血管机制提供了有害的信号平台，从而导致A2在中枢神经系统中积累。

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.