Brain Amyloid and HAND in the cART era

cART时代的脑淀粉样蛋白和HAND

• 批准号: 8992987
• 负责人: CRISTIAN L ACHIM
• 金额: $ 54.59万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-20 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8992987
• 关键词: 3-nitrotyrosine; Adverse effects; Affect; Aging; Alcohol or Other Drugs use; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Anti-Retroviral Agents; Apolipoprotein E; Arterioloscleroses; Autopsy; Blood Vessels; Brain; CDKN2A gene; Cell Aging; Cell Culture Techniques; Cerebrospinal Fluid; Cerebrovascular Circulation; Cerebrum; Chronic; Clinical; Cognitive deficits; Comorbidity; Conditioned Culture Media; Deposition; Detection; Development; Diagnostic; Disease; Etiology; Farnesyl Transferase Inhibitor; Genetic; Genetic Load; Genetic Risk; Genotype; HIV; HIV Envelope Protein gp120; HIV Infections; HIV-1; HIV-associated neurocognitive disorder; Hepatitis C; Hepatitis C virus; Homeostasis; Human; Hyperemia; Immunohistochemistry; In Vitro; Individual; Individual Differences; Infarction; Integration Host Factors; Intervention; Ischemic Stroke; Lamin Type A; Lead; Lesion; Long-Term Survivors; Lopinavir/Ritonavir; Measurement; Measures; Mediating; Metabolic; Microglia; Microvascular Dysfunction; Monitor; N-Acetylcysteinamide; Nerve Degeneration; Neurocognitive Deficit; Neurofibrillary Tangles; Neuropsychological Tests; Outcome; Oxidative Stress; Pathologic; Pathologic Processes; Pathway interactions; Patients; Persons; Phagocytosis; Pharmaceutical Preparations; Phenotype; Predisposition; Process; Protease Inhibitor; Protein Isoforms; Proteins; Recording of previous events; Regimen; Risk; Severities; Smooth Muscle Myocytes; Specimen; Staging; Testing; Toxic effect; Validation; Viral; Viral Load result; Work; abeta accumulation; age related; aging brain; antiretroviral therapy; apolipoprotein E-4; base; brain tissue; cell age; cerebrovascular; cytotoxic; genetic variant; human tissue; macrophage; methamphetamine use; novel; older patient; oxidative damage; prelamin A; premature; protein expression; public health relevance; research study; senescence; targeted treatment; tau Proteins; therapeutic target; white matter

 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.

 描述（由申请人提供）：在当今联合抗逆转录病毒疗法（cART）的时代，HIV相关神经认知障碍（HAND），大多数是较温和的形式，继续影响HIV感染的临床结果，即使是在全身病毒感染的情况下也是如此。这项修订后的提议以我们最近的研究为基础，该研究显示 HIV 感染者大脑中 β-淀粉样蛋白 (Aß) 的积累增加。我们还表明，大脑 Aß 沉积可预测 APOE 中的 HAND。 e4 携带者，在调整每个共病因素后，检测 APOE e4 和脑 Aß 沉积，即脑脊液 (CSF) Aß42 水平降低，可能有助于识别可能受益于 Aß- 的 HAND 受试者。根据我们的发现，HIV 受试者中同皮质 p-Tau 免疫反应性神经原纤维病理学很少，脑脊液 p-Tau 测量可能有用。老年患者中区分 HAND 与阿尔茨海默氏病 (AD) 和其他 tau 蛋白病的方法还包括 HIV 感染和抗逆转录病毒 (ARV) 治疗，尤其是联合治疗。 蛋白酶抑制剂 (ARV-PI) 会增加缺血性中风的风险，包括脑小血管病 (CSVD)。我们的总体假设是，HIV 感染患者的大脑 Aß 斑块沉积与小胶质细胞吞噬功能和血管周围清除功能缺陷有关。一个新的概念是，HIV/ARV-PI 合并症背景下的 CSVD 是由氧化应激诱导的血管过早老化介导的，并且可能是大脑淀粉样蛋白积累的关键基础（通过清除不足）和 HAND 为了测试我们的工作假设，我们制定了 3 个具体目标，从临床病理学和转化验证转向机械干预措施。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）Aß 斑块，并将其与载脂蛋白 E 进行比较。在有或没有 HAND 的受试者中，ApoE（ApoE）和 CSF 测量（-38、-40 和 -42） 我们将研究 200 例 HIV+ 尸检病例的脑淀粉样蛋白负荷，并提供 ART 方案和详细的神经医学史信息。 SA#2：检查 HIV/ARV-PI 共病与人脑血管过早老化、淀粉样蛋白积累和 HAND 之间的关联。 HIV/ARV-PI 共病与血管平滑肌细胞 (VSMC) 中前核纤蛋白 A 积累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作用和 VSMC 衰老的影响。我们认为，VSMC 暴露于 HIV 和 ARV-PI 会诱导氧化应激，导致 Zmpste24 水平降低、prelamin-A 积累增加以及细胞衰老；这些病理过程可能会被特定救援药物的治疗所中断。我们的建议将验证淀粉样蛋白监测对遗传风险增加的个体的诊断价值，并确定与淀粉样蛋白清除有关的潜在治疗靶点。