PREVENTING ALZHEIMER’S DISEASE-LIKE BRAIN PATHOLOGY IN HIV INFECTION BY TARGETING CCR5

通过靶向 CCR5 预防 HIV 感染中的阿尔茨海默病样脑部病变

• 批准号: 10700624
• 负责人: GEORGETTE D. KANMOGNE
• 金额: $ 69.07万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10700624
• 关键词: Abeta synthesis; Address; Alzheimer like pathology; Alzheimer' s Disease; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animal Model; Anti-Retroviral Agents; Area; Autopsy; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Pathology; CCL4 gene; CCR5 gene; Catabolism; Cells; Central Nervous System; Cerebrovascular Trauma; Cerebrovascular system; Development; Down-Regulation; Endocytosis; Endothelium; Enzymes; Functional disorder; Genes; Genetic Transcription; HIV; HIV Infections; HIV-1; HIV-associated neurocognitive disorder; HIV/AIDS; Human; Impaired cognition; Impairment; In Vitro; Individual; Infection; Injury; Interleukin-6; LDL-Receptor Related Protein 1; Lipoproteins; Macrophage; Mediating; Metabolism; Molecular Profiling; Neprilysin; Nerve Degeneration; Neurocognitive Deficit; Neurofibrillary Tangles; Neurons; Pathology; Pathway interactions; Peptide Hydrolases; Persons; Pharmaceutical Preparations; Phosphotransferases; Play; Production; RANTES; Regimen; Research Priority; Role; Senile Plaques; Structure; System; Tenofovir; Testing; Therapeutic; United States National Institutes of Health; Up-Regulation; Vascular Endothelium; Viral Load result; Zidovudine; amyloid formation; amyloid precursor protein processing; amyloidogenesis; antagonist; antiretroviral therapy; beta-site APP cleaving enzyme 1; brain tissue; central nervous system injury; cerebral microvasculature; design; epigenome; epigenomics; humanized mouse; hyperphosphorylated tau; in vivo; neurofibrillary tangle formation; neuroinflammation; neuron loss; neurotoxic; novel; novel therapeutic intervention; prevent; protective effect; receptor; receptor expression; receptor for advanced glycation endproducts; tau Proteins; tau-1; transcriptome; transcriptomics; uptake

PROJECT ABSTRACT Brain tissues from people living with HIV (PLWH) showed evidence of Alzheimer’s Disease (AD)-like pathologies, including increased neurotoxic amyloid-b (Ab40/42), amyloid plaques and Tau hyperphosphorylation (pTau) associated with neurodegeneration and HIV-associated neurocognitive disorders (HAND). The mechanisms through which HIV increase Ab, pTau, and induce AD-like central nervous system (CNS) impairment are not known. Although most PLWH with CNS Ab plaques and pTau had been on long-term antiretroviral therapy (ART), the role of ART in pTau and Ab production, and AD-like pathologies has not been investigated. Findings from our R21 studies, using in vitro, in vivo and ex vivo approaches, demonstrated that HIV-1 significantly increased CNS Ab42 and pTau in humanized mice, and this was associated with significantly 1) increased expression and activation/activity of b-secretase-1 (BACE1), soluble (s)APPb (amyloidogenic pathway effectors), and GSK3b (kinase that phosphorylates Tau); 2) reduced expression/activity of neprilysin (NEP, Ab-degrading enzyme); 3) increased blood-brain barrier (BBB) expression of the receptor for advanced glycation end products (RAGE, mediates Ab CNS influx), and reduced BBB expression of low-density lipoprotein receptor–related protein-1 (LRP1, mediates CNS Ab efflux); and 4) increased neuroinflammation, neuronal damage and BBB injury. We demonstrated that LRP1 and CCR5 mediated Ab transport through the BBB, that AZT potentiated HIV-induced upregulation/activation of BACE1, sAPPb and GSK3b, and that AZT blocked NEP expression/activity. Significantly, the CCR5 antagonist maraviroc (MVC) abrogated these HIV- and AZT- induced effects. Thus, we hypothesize that CCR5, via LRP1, plays a major role in Ab formation, transport, and catabolism, amyloidogenesis and pTau in PLWH, and that targeting CCR5 prevents HIV-induced Ab and pTau, increases Ab CNS efflux, and abrogates CNS injury and HAND. Using a validated HIV/AIDS animal model, primary human cells and human brain tissues, we will test this hypothesis and further investigate the effects of commonly prescribed antiretroviral (ARV) drugs (AZT, TDF) on HIV-induced activation of BACE1 and APP amyloidogenic pathway, Tau metabolism, and CNS injury (Aim-1); Ab transport, degradation, clearance, and neuroinflammation (Aim-2); and associated BBB transcriptomic and epigenomic signatures (Aim-3). These mechanistic studies will help determine whether HIV induces amyloidogenesis by i) activating BACE1 pathways to increase Ab production or ii) by interfering with LRP1-mediated Ab transport, degradation, clearance; iii) the role of ARVs; iv) whether CCR5 modulates these effects; and v) characterize the brain vascular transcriptome and epigenome associated with HIV/ARVs-induced dysregulation and MVC protective effects. Our proposed studies are of high-impact, translational significance, and address the NIH high priority research areas that focus on “Examining the pathophysiologic mechanisms of HIV-induced CNS dysfunction in the setting of ART…and development of novel therapeutic approaches to mitigate CNS complications of HIV infection.”

项目摘要 HIV 感染者 (PLWH) 的脑组织显示出类似阿尔茨海默病 (AD) 的病理学证据， 包括增加神经毒性淀粉样蛋白-b (Ab40/42)、淀粉样斑块和 Tau 过度磷酸化 (pTau) 与神经退行性变和 HIV 相关神经认知障碍 (HAND) 相关。 HIV 不会通过这种方式增加 Ab、pTau 并诱发类似 AD 的中枢神经系统 (CNS) 损伤 尽管大多数患有 CNS Ab 斑块和 pTau 的 PLWH 都在接受长期抗逆转录病毒治疗 (ART)， ART 在 pTau 和 Ab 产生以及 AD 样病理中的作用尚未得到研究。 我们的 R21 研究采用体外、体内和离体方法，证明 HIV-1 显着增加 人源化小鼠中的 CNS Ab42 和 pTau，这与 1) 表达增加和 b-分泌酶-1 (BACE1)、可溶性 (s)APPb（淀粉样蛋白生成途径效应子）和 GSK3b 的激活/活性 （磷酸化 Tau 的激酶）；2) 脑啡肽酶（NEP，抗体降解酶）的表达/活性降低； 晚期糖基化终产物受体（RAGE、 介导 Ab CNS 流入），并减少低密度脂蛋白受体相关蛋白 1 的 BBB 表达 （LRP1，介导 CNS Ab 流出）；4) 增加神经炎症、神经元损伤和 BBB 损伤。 LRP1 和 CCR5 介导抗体通过 BBB 转运，AZT 增强 HIV 诱导的抗体转运 BACE1、sAPPb 和 GSK3b 的上调/激活，并且 AZT 阻断 NEP 表达/活性。 值得注意的是，CCR5 拮抗剂马拉韦罗 (MVC) 消除了这些 HIV 和 AZT 诱导的作用。 因此，我们认为 CCR5 通过 LRP1 在抗体形成、运输和分解代谢中发挥着重要作用， PLWH 中的淀粉样变和 pTau，并且靶向 CCR5 可以预防 HIV 诱导的 Ab 和 pTau， 使用经过验证的 HIV/AIDS 动物模型，增加 Ab CNS 流出，并消除 CNS 损伤和 HAND。 原代人类细胞和人类脑组织，我们将测试这个假设并进一步研究 常用抗逆转录病毒 (ARV) 药物（AZT、TDF）对 HIV 诱导的 BACE1 和 APP 激活的影响 淀粉样蛋白生成途径、Tau 代谢和 CNS 损伤 (Aim-1)；Ab 转运、降解、清除和 神经炎症（Aim-2）；以及相关的 BBB 转录组和表观基因组特征（Aim-3）。 机制研究将有助于确定 HIV 是否通过 i) 激活 BACE1 途径诱导淀粉样蛋白生成 增加抗体产量或 ii) 通过干扰 LRP1 介导的抗体转运、降解、清除 iii) ARV 的作用；iv) CCR5 是否调节这些作用；v) 表征脑血管转录组 以及与 HIV/ARV 引起的失调和 MVC 保护作用相关的表观基因组。 研究具有高影响力、转化意义，并涉及 NIH 重点研究领域 关于“在 ART 背景下检查 HIV 引起的中枢神经系统功能障碍的病理生理机制……以及 开发新的治疗方法来减轻艾滋病毒感染的中枢神经系统并发症。”