Volume 4, Issue 1

Recently there has been a surge in interest involving the application of oligonucleotides, including small interfering RNA (siRNA) and antisense oligonucleotides (ASOs), for the treatment of chronic diseases that have few available therapeutic options. This emerging class of drugs primarily operates by selectively suppressing target genes through antisense and/or RNA interference mechanisms. While various commercial medications exist for delivering oligonucleotides to the hepatic tissue, achieving effective delivery to extra hepatic tissues remains a formidable challenge. Here, we review recent advances in oligonucleotide technologies, including nanoparticle delivery, local administration, and 2′-O-hexadecyl (C16)-conjugation that work to extend the applicability of siRNAs and ASOs to nerve tissues. We discuss critical factors pivotal for the successful clinical translations of these modified or engineered oligonucleotides in the context of treating neurodegenerative diseases such as Alzheimer’s disease and amyotrophic lateral sclerosis.

Introduction Several observational studies reported an association between Rheumatoid Arthritis (RA) and the subsequent risk of developing Parkinson’s disease (PD). However, whether the drugs commonly prescribed for RA contribute to this association remains controversial. Content We sought to summarize all the published evidence regarding the association between the drugs used for RA and the risk of developing PD as well as to explore the potential neuroprotective and therapeutic potential of these drugs for PD patients. We searched three electronic biomedical databases (namely, PubMed, Scopus, and Web of Science) to find potentially relevant studies. The outcome of interest was the relative risk (RR) of developing PD in individuals taking any of these drugs: (1) non-steroidal anti-inflammatory drugs (NSAIDs), (2) acetaminophen, (3) corticosteroids, and (4) disease-modifying anti-rheumatoid drugs (DMARDs), compared to individuals not taking them. Summary and outlook 26 studies (15 case-control and 11 cohort) were included in the analysis with a total number of 4,321,104 participants including 150,703 PD cases. Analysis showed a statistically significant lower risk of developing PD among individuals who received corticosteroids (RR 0.80, 95% CI 0.77 – 0.84, P< 0.00001) and DMARDs (RR 0.69, 95% CI 0.55 – 0.86, P <0.001). Subgroup analysis by individual drugs showed a decreased risk with dexamethasone (RR 0.69, 95% CI 0.60 – 0.79, P <0.00001) and hydroxychloroquine (RR 0.77, 95% CI 0.66 – 0.90, P <0.001). Our findings showed that individuals who were treated with corticosteroids (especially dexamethasone) and DMARDs (especially hydroxychloroquine) have reduced risk of developing PD compared to those not receiving these medications.

Objectives Amyloid-β (Aβ) plaque deposition in the brain is a principal pathological feature of both Alzheimer’s disease (AD) and progressive human immunodeficiency virus type one (HIV-1) infection. Both enable Aβ assembly and Aβ protein aggregation. The potential link between HIV-1 and AD remains uncertain, supporting the need for a reliable animal model. HIV-1 is tropic and pathogenic for humans. It does not replicate in mice. The restricted species tropism has slowed progress in basic research activities. The current study seeks to correct animal model limitations. Methods We created an AD mouse to address the need to develop an small animal model that allows studies of viral infection by making a knock-in (KI) with the human amyloid precursor protein (APP) KM670,671NL Swedish mutation to the mouse genome. The resulting founder mice were crossed with immunodeficient NOG (NOD. Cg- Prkdc scid Il2rg tm1Sug Tg(CMV -IL-34 ) 1 /Jic) to generate NOG/APP KM670,671NL /IL-34 (NAIL) mice. The mice were reconstituted with human hematopoietic stem cells to generate NAIL mice with functional adaptive and innate human immune systems. Four-month-old, humanized NAIL mice were infected with HIV-1 ADA , a macrophage-tropic viral strain then evaluated for viral infection and AD pathology. Results Productive HIV-1 infection was confirmed by plasma HIV-1 RNA levels in infected NAIL mice. The viral load increased by tenfold between day 10 and day 25 post-infection. By day 25, viral DNA confirmed the establishment of HIV-1 reservoirs in CD45+ cells from the immune tissues of infected NAIL mice. Additionally, p24 measurements in lymphoid and brain tissues of NAIL mice validated productive HIV-1 infection. Amyloid burden from infected NAIL mice was increased. Immunofluorescence staining revealed co-localization of Aβ fibrils and HLA-DR + microglia in infected NAIL mice. Conclusions These results highlight the AD-HIV model’s unique pathobiological and infectious features where the viral and immune responses can now be measured.

Objectives HIV-1 enters the central nervous system (CNS) early in infection, and a significant proportion of people with HIV experience CNS complications despite anti-retroviral therapy. Chronic immune dysfunction, inflammatory cytokines and chemokines, and viral proteins like Tat and gp120 released by HIV-1-infected immune cells are implicated in the pathogenesis of HIV-1-associated neurocognitive disorders (HAND). Methods To elucidate the contribution of non-viral factors to CNS complications in people with HIV-1, a comparative analysis of neurovirulent subtype B (HIV-1 ADA ) and non-neurovirulent subtype C (HIV-1 Indie-C1 ) isolates was performed. Culture supernatants from HIV-1-infected PBMCs, either with or without immunodepletion of Tat and gp120, were used to treat SH-SY5Y neuroblastoma cells. Results HIV-1 ADA -infected PBMC media showed significantly higher neurotoxicity than HIV-1 IndieC1 -infected PBMC media, notwithstanding the depletion of Tat and gp120, highlighting the role of non-viral factors (e.g., cytokines) contributing to neurotoxicity. A comparison of inflammatory profiles revealed that HIV-1 ADA media contained elevated levels of cytokines (IL-1α, IL-1β, IL-6 and TNFα) and chemokines (CCL2, CCL3, CCL4 and IP-10). Given the involvement of Tat in upregulating immune mediators, we tested the role of purified Tat proteins from HIV-1 subtypes B and C in inducing an inflammatory phenotype in PBMCs. PBMCs from healthy subjects were treated with recombinant purified Tat from subtype B or C. Subtype B Tat induced a stronger inflammatory response than subtype C Tat. Conclusions These results confirm that both viral and non-viral immune factors mediate neuronal damage in people with HIV.

Objectives A significant clinical concern in the era of Pre-Exposure Prophylaxis (PrEP) is the increased incidence of HIV Anti-Retroviral Drug Resistance Mutations (ARV-DRM). Previous research has indicated that there is an association between substance use and failed viral suppression, which can lead to ARV-DRM. The goal of this retrospective study was to investigate whether substance use as determined by at least one positive urinalysis screen is associated with increased/decreased odds of having a ARV-DRM. Methods This study used firth logistic regression analyses of data retrieved from the National NeuroAIDS Tissue Consortium Data Coordinating Center to examine the relationship between substance use and ARV-DRM. The dataset analyzed 614 participants with the following criteria: HIV+ status, at least one paired plasma and cerebrospinal fluid (CSF) viral load measurement, at least one urinalysis of substance use, at least 18 years of age, and analysis of DRM in CSF/Plasma. Results Cannabis use was a significant predictor of ARV-DRM and was associated with a lower odds of having ARV-DRM (odds ratio=0.189), after accounting for demographic variables and the interaction between polysubstance use and cannabis use. A significant negative relationship was observed between a cannabis positive test and high viremia (>1,000 copies/mL) but not between a cannabis positive test and CSF Escape (viral load CSF>viral load plasma). Conclusions The above results may suggest an immunomodulatory role for cannabis that impacts the propensity for ARV-DRM. These findings could incentivize future research to further investigate effects of cannabis use on the development of HIV ARV-DRM.

Objectives During physical and psychosocial development, many adolescents engage in binge alcohol drinking. Ethanol (EtOH) is the key chemical in alcoholic beverages. EtOH intoxication impairs locomotor behaviors. We previously found that binge treatment with EtOH (BE) causes spleen atrophy, leading to immune dysregulation. With these premises, we hypothesized that BE-induced spleen atrophy is correlated with compromised locomotion and behaviors in adolescence. Methods We exposed F344 rats to either 3 days of BE (mimicking college drinking) or water following pubertal onset. 24 h following the last BE, we assessed behaviors using ANY-Maze, focusing on locomotor activity, freezing, and thigmotaxis, before spleen collection. Correlation analysis and Linear Regression analysis quantified BE’s effects on behavior. In parallel, we used GEO2R to obtain differentially expressed genes (DEGs) from public dataset GSE49028 (B6129Sf2/J mice were given BE) and identified signaling pathways in the prefrontal cortex (PFC) involved in BE compromising locomotion and increasing anxiety. Results BE significantly decreased spleen size. Interestingly, we found that BE exposure had a gender-dependent impact, affecting males more than females. Furthermore, functional analysis of the dataset identified several targets of interest including the downregulation of BDNF as a critical regulator of behavioral deficit following BE treatment. Conclusions Using data-driven discovery and hypothesis-testing investigation to integrate these two studies, we provide an understanding of the underlying biological mechanism of BE-induced spleen atrophy-associated behavioral impairments through the genetic alterations in the PFC. Our findings will help develop a potent, powerful cocktail of reagents to treat behavioral impairment in those who binge drink.

The 29 th Scientific Conference of the Society on Neuroimmune Pharmacology (SNIP) in Omaha, NE, will occur from June 8 th to 11 th , 2025. This four-day conference showcases world-renowned biomedical research, providing insights into the latest advancements in the intersecting fields of neuroscience, immunology, pharmacology, and virology. Presentation abstracts are organized into sections that include early career development investigators, mouse models, neurodegenerative diseases, therapeutics, substance use disorders, counseling, drug targeting, disease pathobiology, Blood-Brain Barrier integrity, educational opportunities, young investigator talks, and translational medicine. SNIP remains the sole global meeting dedicated to neuroimmune pharmacology. The focus of research centers on how the neuroimmune axis connects drug abuse, inflammation, and brain functional integrity. The conference features several plenary speakers who have made unique and significant contributions to their fields alongside renowned physician-scientists and luminaries. Symposia will include the SNIP Presidential Symposium on Pathobiology and Novel Therapies for Neurodegenerative Diseases, Ultra Long-Acting Medicines, Development and Delivery of Diagnostic and Therapeutic Biomarkers to disease regions, overcoming barriers to treating neurological disorders, neuroinflammation, and reward pathways for addiction, as well as neuron-glia interaction. All presentations are framed within the context of microbial infections, drugs of abuse, and therapeutics. Therapeutics include nanopharmacology and advances in informatics analysis of multi-omics data to decipher the complex cell and molecular interactions that underpin the function of the nervous system. SNIP member symposia and a local series of presentations will highlight outstanding talent from the University of Nebraska. Additional events include lunch with NIH program officials and a NeuroImmune Pharmacology and Therapeutics Journal dinner. The goal is to unite investigators from diverse basic, clinical, and translational fields to discuss and advance our understanding of the multifactorial impact of substance abuse, inflammation, and infections critical to human health. We aim to engage and mentor young investigators in neuroimmune pharmacology and disseminate information presented at the conference to the scientific community, the general public, and healthcare providers. Cultivating the next generation of scientists is vital to our mission. The agenda encompasses early-career investigator presentations, poster sessions, meet-the-mentors luncheons, and a special panel of junior faculty. The conference also provides an enriching environment for scientists and clinicians to share ideas, foster the next generation of scientists, and promote current disease pathobiology and therapeutics trends. Opportunities to visit the Omaha zoo will be available with guest passes. We thank Dr. Carol Swarts, the Robert Eisenberg Family, Howard Kooper, the Gendelman Family Research Endowment, Fisher Scientific, Amy Sather, and the research community for sponsoring this meeting and its exchanges.