Brain Amyloid and HAND in the cART era

 描述(申请人提供)：在当前的联合抗逆转录病毒疗法(CART)时代，艾滋病毒相关神经认知障碍(HAND)--主要是较轻微的形式--继续影响艾滋病毒感染的临床结果，即使在全身病毒抑制的情况下也是如此。这项修订后的建议建立在我们最近的研究基础上，该研究表明艾滋病毒感染者的大脑中β-淀粉样蛋白(A？)积累增加。我们还表明，在调整了每个共病因素后，脑Aü沉积对APOE e4携带者中的心脏病有预测作用。因此，检测载脂蛋白e4和脑A？沉积，即脑脊液(CSF)A？42水平的降低，可能有助于确定手部受试者可能受益于A？靶向疗法。根据我们的发现，在HIV受试者中，等皮质p-Tau免疫反应神经原纤维病变稀疏，脑脊液p-Tau测定可能有助于区分手部与阿尔茨海默病(AD)和其他老年患者的变态障碍。众所周知，艾滋病毒感染和抗逆转录病毒(ARV)治疗，特别是在 蛋白水解酶抑制剂(ARV-PI)增加了包括脑小血管疾病(CSVD)在内的缺血性中风的风险。我们的主要假设是，HIV感染患者的大脑Aü斑块沉积与小胶质细胞的吞噬功能缺陷和血管周围清除有关。我们提出了一个新的概念，即在HIV/ARV-PI共同发病的背景下，CSVD是由氧化应激诱导的血管过早老化所介导的，并且可能是脑淀粉样蛋白积累(通过清除不足)和手的关键基础之一。为了验证我们的工作假设，我们制定了3个具体目标，将从临床病理和翻译验证导航到机械干预。SA#1：研究脑斑块、载脂蛋白E4基因与手部疾病的关系。我们将使用定性和半定量IHC来评估大脑(神经周围和血管周围)A？斑块，并将它们与载脂蛋白E(ApoE)和脑脊液中A？亚型(-38、-40和-42)的测量结果进行比较，无论是否有手。我们将研究200例HIV+尸检病例的大脑淀粉样蛋白负荷，并提供ART方案的信息和详细的神经病史。SA#2：检查HIV/ARV-PI共病与人脑血管过早老化、淀粉样蛋白堆积和手的关系。我们认为，HIV/ARV-PI并存与血管平滑肌细胞(VSMC)前层蛋白-A积聚增加和脑血管过早老化有关。SA#3：体外研究ARV-PI对巨噬细胞淀粉样蛋白吞噬和VSMC老化的影响。我们认为，暴露在HIV和ARV-PI下的VSMC会导致氧化应激，导致Zmpste24水平降低，前层蛋白-A积聚增加，细胞衰老；这些病理过程可能会被特定救治药物的治疗中断。我们的建议将验证淀粉样蛋白监测在遗传风险增加的个人的临床标本中的诊断价值，并确定与淀粉样蛋白清除有关的潜在治疗靶点。

 DESCRIPTION (provided by applicant): In the current era of combination antiretroviral therapy (cART), HIV-associated neurocognitive disorders (HAND), mostly in milder forms, continue to affect the clinical outcome of HIV infection, even in the setting of systemic viral suppression. This revised proposal builds on our recent studies showing increased cerebral beta-amyloid (Aß) accumulation in the brains of HIV infected persons. We have also shown that cerebral Aß deposition was predictive of HAND among APOE e4 carriers, after adjusting for each co-morbid factor. Accordingly, the detection of APOE e4 and cerebral Aß deposition, i.e. decreases in cerebro-spinal fluid (CSF) Aß42 levels, may be useful in identifying HAND subjects who may benefit from Aß-targeted therapies. Based on our finding that isocortical p-Tau-immunoreactive neurofibrillary pathology was sparse in HIV subjects, CSF p-Tau measurement may be useful in differentiating HAND from Alzheimer's disease (AD) and other tauopathic disorders in older patients. It is also known that HIV infection and antiretroviral (ARV) treatment, particularly with protease inhibitors (ARV-PI) increase the risk of ischemic stroke, including cerebral small vessel disease (CSVD). Our overarching hypothesis is that cerebral Aß plaque deposition in HIV-infected patients is associated with defective phagocytotic function of microglia and perivascular clearance. We propose a novel concept that CSVD in the context of HIV/ARV-PI co-morbidity is mediated by oxidative stress- induced premature vascular aging and may be one of the key underpinnings of brain amyloid accumulation (via deficient clearance), and HAND. To test our working hypotheses we have formulated 3 specific aims that will navigate from clinico-pathologic and translational validation to mechanistic interventions. SA#1: Study the association between cerebral Aß plaques, ApoE4 genotype and HAND. We will use qualitative and semi- quantitative IHC to assess cerebral (perineuronal and perivascular) Aß plaques and compare them to apolipoprotein E (ApoE), and CSF measurements of Aß isoforms (-38, -40 and -42), in subjects with or without HAND. We will study the cerebral amyloid burden in 200 HIV+ autopsy cases with information on ART regimens and detailed neuromedical history. SA#2: Examine the association between HIV/ARV-PI co-morbidity and premature vascular aging in the human brain, amyloid accumulation, and HAND. We propose that the HIV/ARV-PI co-morbidity is associated with increased prelamin-A accumulation in vascular smooth muscle cells (VSMC) and premature brain vascular aging. SA#3: Investigate in vitro the effects of ARV-PI on macrophage amyloid phagocytosis and VSMC aging. We propose that exposure of VSMC to HIV and ARV-PI induce oxidative stress, leading to reduction in the Zmpste24 level, increased prelamin-A accumulation, and cellular aging; these pathologic processes may be interrupted by treatments with specific rescue drugs. Our proposal will validate the diagnostic value of amyloid monitoring in clinical specimens in individuals with increased genetic risk and identify potential therapeutic targets implicated in amyloid clearance.