# 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

> **NIH NIH R01** · FLORIDA INTERNATIONAL UNIVERSITY · 2021 · $364,202

## Abstract

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 administ...

## Key facts

- **NIH application ID:** 10285175
- **Project number:** 3R01DA052271-02S1
- **Recipient organization:** FLORIDA INTERNATIONAL UNIVERSITY
- **Principal Investigator:** Alexandros Makriyannis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $364,202
- **Award type:** 3
- **Project period:** 2020-07-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10285175

## Citation

> US National Institutes of Health, RePORTER application 10285175, 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 (3R01DA052271-02S1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10285175. Licensed CC0.

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