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 父级R01赠款的主要对象是1）开发，表征和评估艾滋病毒的送达 使用基于MENP的药物输送 消除HIV-1 TAT基因的方法，分别减弱大麻素和TAT诱导的炎性体。 2）研究含有CRISPR的MENP纳米成型的体内治疗效率，并使用AMG315 多西环素诱导的HIV-1 TAT转基因小鼠（ITAT）作为HIV/神经辅助和大麻素给药 动物模型。 3）验证这些纳米成型对神经元可塑性和神经认知的影响 体内功能。母体R01的三个主要重点是HIV，磁电纳米颗粒 （MENP）基于药物的递送和大麻素途径，特别是使用AMG315。我们想在这里 通过评估使用AMG315减轻的潜力来扩大这三个主要重点的范围 NLRP3炎性体介导的神经炎症，淀粉样蛋白和神经纤维缠结病理学的标记 在艾滋病毒和阿尔茨海默氏病（AD）合并症模型中。越来越多的艾滋病毒（PLHIV）的人是 达到老年年龄时，当发展广告的风险达到指数级时，PLHIV具有 分泌有毒蛋白（例如HIV-TAT）的额外燃烧可能解释了普遍的HIV相关的 神经认知障碍（手）。报告了更多被诊断为AD的艾滋病毒感染者的病例。 鉴于类似于Aβ，HIV-TAT蛋白可以激活炎症体，增加Aβ水平，这并不奇怪。 通过抑制Neprilysin并增强BACE活动，从而使HIV和AD合并症患者易于 协同作用。不幸的是，到目前为止，艾滋病毒手或 AD中的记忆问题，包括使用大麻素的临床试验，尽管内源性大麻素 已知系统（EC）在记忆中起着基本作用。 ECS配体的失败主要是由于较差 药代动力学尤其是化合物的短期。稳定的最大挑战是成功的 由我们的Co-I发现Alexandros Makriyannis博士通过发现AMG315，这是一种潜力，更稳定的CB1 受体配体。因此，在特定的目标1中，类似于父r01，使用Menp纳米制剂（NF），我们将 通过i.v.管理AMG315，甲烷酰胺（用于比较）或车辆路线和评估是否AMG315 可以减轻艾滋病毒和广告合并症的焦点小鼠模型中的炎性介导的神经炎症， 3xtg/itat。在特定目标2中，我们将验证AMG315是否可以减少淀粉样斑块和神经纤维 缠结燃烧并与改善的记忆相关。由于我们计划直接在鼠标中测试AMG315 艾滋病毒（ITAT）和AD（3XTG）的模型，并解决艾滋病毒/广告研究中的三个关键问题，即艾滋病毒和aD 合并症，大麻素多白素途径和有效的大脑渗透，这种行政补充 要求与阿尔茨海默氏病和相关痴呆症（ADRD）直接相关。如果AMG315有益 在合并症模型中的影响，在这项研究中，可以进一步开发用于未来研究的临床用途。