Brain Amyloid and HAND in the cART era

cART时代的脑淀粉样蛋白和HAND

• 批准号: 9274371
• 负责人: CRISTIAN L ACHIM
• 金额: $ 47.32万
• 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/9274371
• 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; Autopsy; Blood Vessels; Brain; CDKN2A gene; Cell Aging; Cell Culture Techniques; Cerebral small vessel disease; 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 antiretroviral; HIV-1; HIV-associated neurocognitive disorder; Hepatitis C; Homeostasis; Human; Hyperemia; Immunohistochemistry; In Vitro; Individual; Individual Differences; Infarction; Integration Host Factors; Interruption; Intervention; Ischemic Stroke; Lamin Type A; Lead; Lesion; Long-Term Survivors; Lopinavir/Ritonavir; Measurement; Measures; Mediating; Metabolic; Microglia; Monitor; Muscle Cells; N-Acetylcysteinamide; Nerve Degeneration; Neurocognitive Deficit; Neurofibrillary Tangles; Neuropsychological Tests; Outcome; Oxidative Stress; Pathogenicity; Pathologic; Pathologic Processes; Pathway interactions; Patients; Persons; Phagocytosis; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Predisposition; Process; Protease Inhibitor; Protein Isoforms; Proteins; Recording of previous events; Regimen; Risk; Severities; Specimen; Testing; Toxic effect; Validation; Vascular Smooth Muscle; Viral; Viral Load result; abeta accumulation; abeta deposition; aging brain; antiretroviral therapy; apolipoprotein E-4; base; brain tissue; cerebrovascular; cytotoxic; experimental study; genetic variant; human tissue; immunoreactivity; macrophage; methamphetamine use; novel; older patient; oxidative damage; prelamin A; premature; protein expression; public health relevance; 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）：在当前的联合抗逆转录病毒治疗（cART）时代，HIV相关神经认知障碍（HAND）（大多为轻度形式）继续影响HIV感染的临床结局，即使在全身性病毒抑制的情况下也是如此。这项修订建议建立在我们最近的研究基础上，这些研究表明，艾滋病毒感染者大脑中的β淀粉样蛋白（A β）积累增加。我们还表明，在调整了每种共病因素后，脑内ARAP4沉积可预测APOE e4携带者的HAND。因此，检测APOE e4和脑ApoE沉积，即脑脊液（CSF）A β 42水平的降低，可用于鉴定可受益于ApoE靶向治疗的HAND受试者。基于我们发现HIV受试者中等皮质p-Tau免疫反应性神经病理学稀少，CSF p-Tau测量可能有助于区分HAND与老年患者中的阿尔茨海默病（AD）和其他tau病变。众所周知，艾滋病毒感染和抗逆转录病毒（ARV）治疗，特别是 蛋白酶抑制剂（ARV-PI）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感染患者的脑Ablation斑块沉积与小胶质细胞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共病背景下的CSVD是由氧化应激诱导的过早血管老化介导的，并且可能是脑淀粉样蛋白积聚（通过清除不足）和HAND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，将从临床病理和转化验证导航到机械干预。SA#1：研究脑ApoE斑块、ApoE 4基因型和HAND之间的关联。我们将使用定性和半定量IHC来评估脑（神经元周围和血管周围）ApoE斑块，并将其与载脂蛋白E（ApoE）和CSF中ApoE亚型（-38、-40和-42）的测量值（在有或无HAND的受试者中）进行比较。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治疗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、淀粉样蛋白蓄积和HAND之间的关联。我们认为HIV/ARV-PI共病与血管平滑肌细胞（VSMC）中前层蛋白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老化的影响。我们认为，暴露于HIV和ARV-PI诱导VSMC氧化应激，导致Zmpste24水平降低，增加prelamin-A积累和细胞老化;这些病理过程可能会中断与特定的救援药物治疗。我们的提案将验证淀粉样蛋白监测在遗传风险增加的个体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。