Altered Amyloid Processing HIV

描述(由申请人提供)：艾滋病毒感染者的神经认知障碍，统称为艾滋病毒相关神经认知障碍(或手)在联合抗逆转录病毒治疗(CART)时代仍然是一个严重的问题。在许多HIV感染者中，有证据表明衰老加速，包括淀粉样前体蛋白(APP)的异常处理。这些干扰似乎导致致病形式的淀粉样蛋白(A？)在大脑中积聚，因此也可能减少重要的神经营养肽--可溶性APP？(Sapp？)的形成。我们的初步数据表明，神经鞘脂脂和复合糖脂在细胞内的积聚通过增强？和？-分泌酶的活性(这一过程适用于A？)和通过扰乱A？的细胞内运输/清除来加速A？的形成。在此之前，我们已经记录了HIV感染者体内多种鞘脂物种的积累。这些综合的发现促使我们确定在内体、溶酶体和/或自噬体内积累的鞘磷脂产物是否与HIV感染环境中异常的APP处理、A？沉积增加和SAPP？减少有关。在这项应用中，我们提出了一种综合的方法来解决这个问题，使用人脑组织、细胞/分子方法和转基因模型系统来确定这些脂代谢产物的大脑水平增加是否会将APP处理转变为更多的淀粉样变性(A？)和更少的营养(SAP)型，以及针对鞘磷脂代谢的干预是否可以逆转这些影响。))

DESCRIPTION (provided by applicant): Neurocognitive impairments in HIV-infected individuals, collectively known as HIV-Associated Neurocognitive Impairments (or HAND) remains a significant problem in the era of Combined Antiretroviral Therapy (CART). In many HIV-infected individuals there is evidence of accelerated aging, including aberrant processing of amyloid precursor protein (APP). These disruptions seem to result in accumulations of pathogenic forms of amyloid-¿ (A¿) in brain and are thus likely to also decrease the formation of soluble APP¿ (sAPP¿), an important neurotrophic peptide. Our preliminary data suggest that accumulations of sphingolipids and complex glycolipids in intracellular compartments accelerates A¿ formation by enhancing the activity of ¿- and ?- secretases (that process APP to A¿), and by perturbing the intracellular trafficking / clearance of A¿. Previously we have documented accumulations of multiple sphingolipid species in HIV-infected individuals. These combined findings prompted us to determine if the accumulations of sphingolipid products in endosomes, lysosomes and/or autophagosomes are associated with aberrant APP processing, increased A¿ deposition and decreased sAPP¿ in the setting of HIV-infection. In this application we propose a comprehensive approach to address this question, using human brain tissues, cellular/molecular approaches, and transgenic model systems to determine if increased brain levels of these lipid metabolites shifts APP processing to a more amyloidogenic (A¿) and less trophic (sAPP¿) pheotype and if interventions that target sphingolipid metabolism can reverse these effects. ) )