Effect of a potent and metabolically stable endocannabinoid receptor agonist on inflammasome-induced neuroinflammation in a comorbid mouse model of Alzheimer's disease and HIV

一种有效且代谢稳定的内源性大麻素受体激动剂对阿尔茨海默病和艾滋病毒共病小鼠模型中炎症小体诱导的神经炎症的影响

• 批准号: 10285175
• 负责人: Alexandros Makriyannis
• 金额: $ 36.42万
• 依托单位: FLORIDA INTERNATIONAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10285175
• 关键词: 3xTg-AD mouse; ABHD6 gene; Address; Administrative Supplement; Adverse effects; Age; Agonist; Alleles; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Animal Model; Antiinflammatory Effect; Attenuated; Binding; Biological; Blood - brain barrier anatomy; Brain; CNR1 gene; CRISPR/Cas technology; Cannabinoids; Clinical; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Conduct Clinical Trials; Dementia; Development; Diagnosis; Diffuse; Disease; Doxycycline; Drug Delivery Systems; Drug Kinetics; Elderly; Endocannabinoids; Enzymes; Face; Failure; Future; General Population; Generations; Grant; Guide RNA; HIV; HIV tat Protein; HIV-1; HIV-associated neurocognitive disorder; In Vitro; Individual; Inflammasome; Inflammatory; Lead; Learning; Life; Life Expectancy; Ligands; Liposomes; Mediating; Memory; Memory impairment; Metabolic; Modeling; Mus; Nature; Neprilysin; Neurocognitive; Neurocognitive Deficit; Neurofibrillary Tangles; Neuronal Plasticity; PTGS2 gene; Parents; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Penetration; Pharmaceutical Preparations; Physiological; Plasma; Play; Population; Proteins; RNA; Receptor Signaling; Recovery; Reporting; Research; Risk; Role; Route; Senile Plaques; Signal Transduction; Technology; Testing; Therapeutic; Time; Transgenic Mice; Treatment Efficacy; United States National Institutes of Health; antiretroviral therapy; apolipoprotein E-4; base; beta-site APP cleaving enzyme 1; cannabinoid receptor; cannabinoid receptor antagonist; comorbidity; cytokine; drug candidate; effective therapy; endogenous cannabinoid system; genetic risk factor; geriatric neuroHIV; improved; in vivo; meetings; memory process; methanandamide; mild cognitive impairment; mouse model; nanoformulation; nanoparticle; neuroAIDS; neuroinflammation; novel; receptor; response; success; tat Genes; tau Proteins; therapeutic target; treatment strategy

PROJECT SUMMARY of the administrative supplement The major objectives of the parent R01 grant are 1) to develop, characterize, and evaluate the delivery of HIV Tat-specific CRISPR Cas9/gRNA and AMG315 across the in vitro BBB using the MENP-based drug delivery approach to excise HIV-1 Tat gene, and attenuate cannabinoid and Tat-induced inflammasome, respectively. 2) to study the in vivo therapeutic efficacy of MENP nanoformulation containing CRISPR, and AMG315 using doxycycline-inducible HIV-1 Tat transgenic mice (iTat) as an HIV/neuroAIDS and cannabinoid administration animal model. 3) to validate the effects of these nanoformulations on neuronal plasticity and neurocognitive functions in vivo. Thus the three major focuses in the parent R01 are HIV, magneto-electric nanoparticle (MENP)-based drug delivery, and the cannabinoid pathway, in particular the use of AMG315. Here we want to broaden the scope of these three major focuses by also evaluating the potential of using AMG315 to mitigate NLRP3 inflammasome-mediated markers of neuroinflammation, amyloid, and neurofibrillary tangle pathology in a comorbidity model of HIV and Alzheimer’s disease (AD). As more people living with HIV (PLHIV) are reaching geriatric ages when the risk of developing AD reaches exponential proportion, PLHIV has an additional burden of secreting toxic proteins such as HIV-Tat that might explain the prevalent HIV-associated neurocognitive disorder (HAND). More cases of HIV-infected individuals diagnosed with AD are being reported. This is not surprising given that similar to Aβ, HIV-Tat protein can activate inflammasome, increase Aβ levels by inhibiting neprilysin and enhancing BACE activity thereby predisposing HIV and AD comorbid patients for synergistic effects. Unfortunately, there has been no therapeutic success so far either for HIV-HAND or memory issues in AD, including clinical trials using cannabinoid compounds, although the endocannabinoid system (ECS) is known to play a fundamental role in memory. The failure of ECS ligands is mainly due to poor pharmacokinetics especially the short-life of compounds. This greatest challenge of stability was successfully addressed by our Co-I, Dr. Alexandros Makriyannis by discovering AMG315, a potent and more stable CB1 receptor ligand. Therefore in Specific Aim 1, similar to parent R01, using MENP nanoformulation (NF) we will administer AMG315, methanandamide (for comparison), or vehicle by i.v. route and assess whether AMG315 can mitigate inflammasome-mediated neuroinflammation in a bigenic mouse model of HIV and AD comorbidity, 3xTg/iTat. In Specific Aim 2, we will verify whether AMG315 can reduce amyloid plaque and neurofibrillary tangle burden and correlate with improved memory. Since we plan to test the AMG315 directly in a mouse model of HIV (iTAT) and AD (3xTg) and address three key questions in HIV/AD research, i.e., HIV and AD comorbidity, cannabinoid multitarget pathway, and efficient brain penetration, this administrative supplement request is directly related to Alzheimer’s disease and related dementias (ADRD). If AMG315 has beneficial effects in the comorbidity model in this study, it may be further developed for clinical use in future studies.

行政补充的项目摘要 母公司 R01 资助的主要目标是 1) 开发、描述和评估 HIV 的传播 使用基于 MENP 的药物递送跨体外 BBB 的 Tat 特异性 CRISPR Cas9/gRNA 和 AMG315 方法切除 HIV-1 Tat 基因，并分别减弱大麻素和 Tat 诱导的炎症小体。 2) 使用含有CRISPR和AMG315的MENP纳米制剂研究体内治疗效果 多西环素诱导的 HIV-1 Tat 转基因小鼠（iTat）作为 HIV/神经艾滋病和大麻素给药 3) 验证这些纳米制剂对神经元可塑性和神经认知的影响。 因此，母体 R01 的三个主要焦点是 HIV、磁电纳米颗粒。 基于 MENP 的药物输送和大麻素途径，特别是 AMG315 的使用。 通过评估使用 AMG315 缓解压力的潜力，扩大了这三个主要关注点的范围 NLRP3 炎症小体介导的神经炎症、淀粉样蛋白和神经原纤维缠结病理学标志物 随着越来越多的艾滋病毒感染者 (PLHIV) 出现，艾滋病毒和阿尔茨海默病 (AD) 的共病模型中。 到了老年，当患 AD 的风险达到指数比例时，艾滋病毒携带者 分泌有毒蛋白质（例如 HIV-Tat）的额外负担可能解释了与 HIV 相关的普遍现象 越来越多的 HIV 感染者被诊断为 AD 病例。 这并不奇怪，因为与 Aβ 类似，HIV-Tat 蛋白可以激活炎症小体，增加 Aβ 水平 通过抑制脑啡肽酶并增强 BACE 活性，使 HIV 患者易感，从而导致 AD 共病患者 不幸的是，迄今为止，HIV-HAND 或 HIV-HAND 的治疗尚未取得成功。 AD 中的记忆问题，包括使用大麻素化合物的临床试验，尽管内源性大麻素 已知ECS系统（ECS）在记忆中发挥着基础性作用，ECS配体的失败主要是由于不良。 药代动力学，特别是化合物的短寿命，成功地解决了稳定性这一最大的挑战。 我们的 Co-I Alexandros Makriyannis 博士发现了 AMG315，一种有效且更稳定的 CB1 因此，在特定目标 1 中，与母体 R01 类似，我们将使用 MENP 纳米制剂 (NF)。 通过静脉注射途径施用 AMG315、甲烷酰胺（用于比较）或载体，并评估 AMG315 是否有效。 可以减轻 HIV 和 AD 共病双基因小鼠模型中炎症体介导的神经炎症， 3xTg/iTat 在具体目标2中，我们将验证AMG315是否可以减少淀粉样斑块和神经原纤维。 由于我们计划直接在鼠标中测试 AMG315，因此它可以减轻缠结负担并与记忆力提高相关。 HIV (iTAT) 和 AD (3xTg) 模型并解决 HIV/AD 研究中的三个关键问题，即 HIV 和 AD 合并症、大麻素多靶点途径和有效的大脑渗透，该行政补充 如果 AMG315 具有有益作用，则该要求与阿尔茨海默病和相关痴呆症 (ADRD) 直接相关。 由于本研究中合并症模型的影响，它可能会在未来的研究中进一步开发用于临床应用。