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.

行政增刊项目摘要