Altered Amyloid Processing HIV

描述（由申请人提供）：hiv感染者的神经认知障碍，统称为hiv相关神经认知障碍（HAND），仍然是抗逆转录病毒联合治疗（CART）时代的一个重要问题。在许多hiv感染者中，有证据表明衰老加速，包括淀粉样蛋白前体蛋白（APP）的异常加工。这些破坏似乎导致淀粉样蛋白- (A)在大脑中致病性形式的积累，因此也可能减少可溶性APP - (sAPP)的形成，这是一种重要的神经营养肽。我们的初步数据表明鞘脂和复合糖脂在细胞内区室的积累通过增强-和？的活性来加速A ?的形成。-分泌酶（将APP转化为A¿），并通过扰乱细胞内A¿的运输/清除。以前我们已经记录了hiv感染个体中多种鞘脂的积累。这些综合发现促使我们确定鞘脂产物在内体、溶酶体和/或自噬体中的积累是否与hiv感染情况下异常的APP加工、A¿沉积增加和sAPP¿减少有关。在本应用中，我们提出了一种全面的方法来解决这个问题，使用人类脑组织，细胞/分子方法和转基因模型系统来确定这些脂质代谢物的大脑水平增加是否会将APP加工转变为淀粉样蛋白（a¿）和营养（sAPP¿）表型，以及针对鞘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. ) )