Receptors, Volume 4, Issue 1 (March 2025) – 7 articles

Background/Objectives: Alzheimer’s disease (AD) severely hinders cognitive function in the hippocampus (HP) and subiculum (SUB), impacting the expression of nicotinic acetylcholine receptors (nAChRs) such as the α7-subtype. To investigate α7 nAChRs as a potential PET imaging biomarker, we report the quantitative binding of [¹²⁵I]α-Bungarotoxin ([¹²⁵I]α-Bgtx) for binding to postmortem human AD (n = 29; 13 males, 16 females) HP compared to cognitively normal (CN) (n = 28; 13 male, 15 female) HP. Methods: For comparisons with common AD biomarkers, adjacent slices were anti-Aβ and anti-Tau immunostained for analysis using QuPath. Results: The [¹²⁵I]α-Bgtx average SUB/HP ratio was 0.5 among the CN subjects, suggesting higher [¹²⁵I]α-Bgtx binding in the HP gray matter regions. The AD subjects showed overall less binding than the CN subjects, with no statistical significance. A positive correlation was found in the [¹²⁵I]α-Bgtx binding in the AD subjects as the age increased. The Braak stage comparisons of [¹²⁵I]α-Bgtx were made with [¹⁸F]flotaza binding to Aβ plaques and [¹²⁵I]IPPI binding to Tau. A positive correlation was found between [¹²⁵I]α-Bgtx and [¹⁸F]flotaza and there was a negative correlation between [¹²⁵I]α-Bgtx and [¹²⁵I]IPPI, implicating intricate relationships between the different AD biomarkers. Conclusions: [¹²⁵I]α-Bgtx shows complimentary potential as a α7 nAChR imaging agent but needs more preclinical assessments to confirm effectiveness for translational PET studies using α7 nAChR radioligands. Full article

Background: Detecting intracellular diffusion dynamics with high spatiotemporal resolution is critical for understanding the complex molecular mechanisms that govern viral infection, drug delivery, and sustained receptor signaling within cellular compartments. Although considerable progress has been made, accurately distinguishing between different types of diffusion in three dimensions remains a significant challenge. Methods: This study extends a previously established two-dimensional, machine learning-based diffusional fingerprinting approach into a three-dimensional framework to overcome this limitation. It presents an algorithm that predicts intracellular motion types based on a comprehensive feature set, including custom statistical descriptors and standard Imaris-derived trajectory features, which capture subtle variations in individual trajectories. The approach employs an extended gradient-boosted decision trees classifier trained on an array of synthetic trajectories designed to simulate diffusion behaviors typical of intracellular environments. Results: The machine learning classifier demonstrated a classification accuracy of over 90% on synthetic datasets, effectively capturing and distinguishing complex diffusion patterns. Subsequent validation using an experimental dataset confirmed the robustness of the approach. The incorporation of the Imaris track features streamlined diffusion classification and enhanced adaptability across diverse volumetric imaging modalities. Conclusions: This work advances our ability to classify intracellular diffusion dynamics in three dimensions and provides a method that is well-suited for high-resolution analysis of intracellular receptor trafficking, intracellular transport of pathogenic agents, and drug delivery mechanisms. Full article

The body’s physiology during physical injuries and diseases depends heavily on the function of acute inflammation. On the other hand, many variables, including iatrogenic, immune system deficiencies, lifestyle, and social and environmental factors, are significant in developing systemic chronic inflammation (SCI). SCI is a major contributor to many diseases and a global cause of death and disability. Therefore, in the present article, we suggest integrative strategies for preventing SCI by addressing receptor overexpression and promoting health improvement. With the objective of reducing chronic inflammation by regulating cytokines, chemokines, and receptor modulation to try to reduce the risk of developing systemic chronic inflammatory diseases (also known as chronic-degenerative diseases, such as diabetes mellitus, cancer, cardiovascular disease, stroke, chronic kidney disease, neurodegenerative disorders, autoimmune diseases, and psychiatric disorders), the strategies we suggest are dietary modifications, exercise, and meditation. Accordingly, the prevention of SCI can be approached holistically with the help of the previous strategies, which may substantially impact public health. Full article

The retinal network relies on glutamate, the primary excitatory neurotransmitter involved in the visual cycle. Glutamate transactions are carried out by an array of distinct receptors and transporters distributed across both pre- and post-synaptic neurons and Müller radial glial cells. Glutamate receptors are broadly divided into two types: ionotropic and metabotropic receptors that differ in their molecular architecture and signaling properties. Within the retina, Müller glia cells span across its entire layers and possess specialized features that enable them to regulate glutamate extracellular levels and thus, its neuronal availability. In order to prevent an excitotoxic insult, retina extracellular glutamate levels have to be tightly regulated through uptake, predominantly into Müller glial cells, by a family of Na⁺-dependent glutamate transporters known as excitatory amino acid transporters. An exquisite interplay between glutamate receptor signaling and glutamate transporter expression and function is fundamental for the integrity and proper function of the retina. This review examines our current understanding of the impact of Müller glial glutamate signaling on glia/neuronal coupling. Full article

Background: External guide sequences (EGSs) are small RNA molecules capable of hybridizing to a target mRNA and rendering the target RNA susceptible to degradation by ribonuclease P (RNase P), a tRNA processing enzyme. Methods: In this study, natural tRNA-originated and engineered variant EGSs were constructed to target the mRNA encoding human CC-chemokine receptor 5 (CCR5), an HIV co-receptor. Results: The EGS variant was about 100-fold more efficient in inducing RNase P-mediated cleavage of the CCR5 mRNA sequence in vitro than a natural tRNA-derived EGS. Furthermore, the expressed variant and natural tRNA-originated EGSs decreased CCR5 expression by 98% and 73–77% and reduced infection by the CCR5-tropic HIV_Ba-L strain in cells by more than 900- and 50-fold, respectively. By contrast, cells expressing these EGSs exhibited no change in the expression of CXCR4, another HIV co-receptor, and showed no reduction in infection by the CXCR4-tropic HIV_IIIB strain, which uses CXCR4 instead of CCR5 as the co-receptor. Thus, the EGSs specifically targeted CCR5 but not CXCR4. Conclusions: Our results demonstrate that EGSs are effective and specific in diminishing HIV infection and represent a novel class of gene-targeting agents for anti-HIV therapy. Full article

Glucagon-like peptide-1 receptor agonists (GLP-1RAs), including dulaglutide, liraglutide, semaglutide, and exenatide, are effective treatments for type 2 diabetes mellitus (T2DM) and obesity. These agents mimic the action of the endogenous incretin glucagon-like peptide-1 (GLP-1) by enhancing insulin secretion, inhibiting glucagon release, and promoting weight loss through appetite suppression. GLP-1RAs have recently been suggested to have neuroprotective effects, suggesting their potential as treatment for neurodegenerative disorders, such as Alzheimer’s disease (AD). AD and T2DM share several common pathophysiological mechanisms, including insulin resistance, chronic inflammation, oxidative stress, and mitochondrial dysfunction. These shared mechanisms suggest that therapeutic agents targeting metabolic dysfunction may also be beneficial for neurodegenerative conditions. Preclinical studies on GLP-1RAs in AD models, both in vitro and in vivo, have demonstrated promising neuroprotective effects, including reductions in amyloid-beta accumulation, decreased tau hyperphosphorylation, improved synaptic plasticity, and enhanced neuronal survival. Despite the encouraging results from preclinical models, several challenges need to be addressed before GLP-1RAs can be widely used for AD treatment. Ongoing clinical trials are investigating the potential cognitive benefits of GLP-1RAs in AD patients, aiming to establish their role as a therapeutic option for AD. This review aimed to examine the current literature on preclinical and clinical studies investigating GLP-1 receptor agonists as potential therapeutic agents for AD. Full article

The increased prevalence of electronic cigarettes, particularly among adolescents, has escalated concerns about nicotine addiction. Nicotine, a potent psychostimulant found in tobacco products, exerts its effects by interacting with nicotinic acetylcholine receptors (nAChRs) in the brain. Recent findings in both pre-clinical and clinical studies have enhanced our understanding of nAChRs, overcoming the limitations of pharmacological tools that previously hindered their investigation. Of particular interest is the α6 subunit, whose expression peaks during adolescence, a critical period of brain development often marked by the initiation of substance use. Pre-clinical studies have linked α6-containing nAChRs (α6*nAChRs) to nicotine-induced locomotion, dopamine release, and self-administration behavior. Furthermore, clinical studies suggest an association between the α6 subunit and increased smoking behavior in humans. Specifically, a single nucleotide polymorphism in the 3′ untranslated region of the CHRNA6 gene that encodes for this subunit is linked to smoking behavior and other substance use. A comprehensive understanding of this subunit’s role in addiction is of high importance. This review aims to consolidate current knowledge regarding the α6 subunit’s functions and implications in addiction and other disorders, with the hope of paving the way for future research and the development of targeted therapies to address this pressing public health concern. Full article