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.

行政补助金项目摘要 母R 01赠款的主要目标是：1）开发、表征和评估艾滋病毒的交付 Tat特异性CRISPR Cas9/gRNA和AMG 315使用基于MENP的药物递送穿过体外BBB 切除HIV-1达特基因，分别减弱大麻素和塔特诱导的炎性小体。 2)研究含有CRISPR和AMG 315的MENP纳米制剂的体内治疗功效， 作为HIV/neuroAIDS和大麻素给药的多西环素诱导的HIV-1达特转基因小鼠（i达特） 动物模型3)为了验证这些纳米制剂对神经元可塑性和神经认知的影响， 在体内发挥作用。因此，母体R 01中的三个主要焦点是HIV、磁电纳米颗粒 （MENP）的药物递送和大麻素途径，特别是AMG 315的使用。这里我们要 扩大这三个主要重点的范围，同时评估使用AMG 315缓解 NLRP 3炎性体介导的神经炎症、淀粉样蛋白和神经系统缠结病理学标志物 在HIV和阿尔茨海默病（AD）的共病模型中。随着越来越多的艾滋病毒感染者（PLHIV） 当发展成AD的风险达到指数比例时，达到老年年龄时， 分泌有毒蛋白质的额外负担，如HIV-Tat，这可能解释了流行的HIV相关性 神经认知障碍（HAND）。越来越多的艾滋病毒感染者被诊断为AD。 这并不奇怪，因为与Aβ类似，HIV-Tat蛋白可以激活炎性小体，增加Aβ水平， 通过抑制脑啡肽酶和增强BACE活性，从而使HIV和AD共病患者易患 协同效应不幸的是，到目前为止，无论是对艾滋病毒手， AD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 众所周知，ECS系统在存储器中起着重要作用。ECS配体的失败主要是由于差的 药代动力学，特别是化合物的短寿命。这一最大的稳定性挑战成功地 我们的首席执行官Alexandros Makriyannis博士发现了AMG 315，一种有效且更稳定的CB 1 受体配体因此，在特定目标1中，与母体R 01相似，使用MENP纳米制剂（NF），我们将 通过i. v.途径给予AMG 315、甲雄胺（用于比较）或溶媒，并评估AMG 315是否 可以减轻HIV和AD共病双基因小鼠模型中炎性小体介导的神经炎症， 3xTg/iTat。在具体目标2中，我们将验证AMG 315是否可以减少淀粉样斑块和神经胶质瘤。 并与记忆力提高相关。由于我们计划直接在小鼠中测试AMG 315， HIV（iTAT）和AD（3xTg）的模型，并解决HIV/AD研究中的三个关键问题，即，艾滋病毒和AD 共病、大麻素多靶点途径和有效的大脑渗透，这份行政补充 阿尔茨海默病和相关痴呆症（ADRD）直接相关。如果AMG 315具有有益的 在本研究的合并症模型中，它可能会在未来的研究中进一步开发用于临床。