ACS Chemical Neuroscience最新文献

The gut microbiota influences neurodegenerative disease progression, including Alzheimer’s disease (AD), through microbial metabolites like amyloids in bacterial biofilms, such as the curli protein in Eshcherichia coli biofilm. In this context, the study focuses on two key aspects, namely, (i) how cross-kingdom bacterial biofilm proteins accelerate Aβ42 aggregation and induce neurotoxicity and (ii) whether a nanochaperone with hydrophobic sheets and hydrophilic polyphenolic moieties could inhibit cross-seeded aggregation. Considering this, we chemically synthesized and further characterized gallic acid-conjugated molybdenum disulfide quantum dots (GA@MoS₂ QDs, ∼9.6 ± 4.2 nm) using spectroscopy and microscopy techniques, which showed ∼1.84-fold reduction in E. coli biofilm thickness, indicating interaction with biofilm components. The presence of the curli protein in E. coli was confirmed by dot blot and MALDI-TOF studies. Subsequent biophysical studies showed that isolated E. coli biofilm protein accelerated Aβ42 aggregation (heterotypic) by ∼6.76-fold, while GA@MoS₂ QDs reduced this heterotypic aggregation by ∼9.49-fold reduction in Aβ42+EC_BFP fluorescence relative to Aβ42 aggregates. In vitro studies with SH-SY5Y cells showed that heterotypic protein aggregation led to increased ROS production, intracellular calcium influx, and apoptosis induction, which were mitigated by GA@MoS₂ QDs. The neuroprotective effect of GA@MoS₂ QDs was also studied on Caenorhabditis elegans. Overall, the present studies suggested that the bacterial amyloid proteins may play a crucial role in Aβ42 aggregation, suggesting that targeting coaggregation could provide a novel therapeutic approach for the treatment of early onset AD.

Electrochemical sensors rely on reference electrodes (REs) to provide stable potential standards, ensuring accurate and reliable detection. The development of biocompatible, stable, and miniaturized REs to replace conventional Ag/AgCl electrodes is crucial for translating electrochemical sensing for human applications. This study evaluates the performance of thin-film electrodes made from gold (Au), platinum (Pt), poly(3,4-ethylenedioxythiophene)-polystyrenesulfonate (PEDOT:PSS), and platinum–iridium (Pt–Ir) as REs for fast-scan cyclic voltammetry (FSCV), a widely used technique for real-time neurotransmitter detection. Using dopamine (DA) sensing as a model platform, our results demonstrate that Pt–Ir electrodes provide the necessary stable potential, low drift, and high reproducibility for FSCV sensing, even at a reduced size of 0.1 mm × 0.1 mm. Additionally, Pt–Ir exhibited performance comparable to Ag/AgCl electrodes across various pH levels and in the presence of biofouling agents. These findings highlight Pt–Ir as a promising alternative RE, with strong potential for integration into miniaturized electrochemical sensors for both preclinical and clinical applications.

Self-aggregation of amyloid-β (Aβ) peptide plays a key role in the pathogenesis of Alzheimer’s disease (AD), the most prevalent cause of dementia affecting the elderly population. The development of an effective treatment for AD pathology remains elusive due to the presence of the blood-brain barrier (BBB) and the heterogeneous nature of disease progression. Recently, we reported that FDA-approved native poly(d,l-lactic-co-glycolic acid) (PLGA) nanoparticles without any conjugated/encapsulated agent can attenuate Aβ aggregation/toxicity in cellular and animal models of AD. Given the limitation associated with the fast clearance of the native PLGA by the reticuloendothelial system (RES), in the present study, we synthesized PEGylated native PLGA nanoparticles (PEG–PLGA-1) to reduce their clearance via the RES and evaluated their effects on Aβ aggregation/toxicity after biochemical and structural characterization. Determined with Thioflavin T kinetic assay, dynamic light scattering and fluorescence imaging, it was revealed that the native PEG–PLGA-1, which exhibits increased stability, not only inhibits the aggregation of Aβ peptides, but also triggers the disassembly of Aβ aggregates. Additionally, we showed that PEG–PLGA-1 are nontoxic and can significantly enhance the viability of mouse primary cortical cultured neurons against Aβ-mediated toxicity. Collectively, these results suggest that native PEG–PLGA-1 nanoparticles can inhibit Aβ aggregation and trigger disassembly of Aβ aggregates and can protect neurons against Aβ-mediated toxicity, thus suggesting their unique therapeutic potential in the treatment of AD pathology.

Surfaces coated with the hyperbranched dendritic polyglycerol amine, dPGA, a nonprotein macromolecular biomimetic of polylysine, have been shown to provide enhanced support for stable long-term culture of embryonic rat neocortical neurons and human neurons derived from induced pluripotent stem cells (iPSCs). Here, we investigate the physical properties of surface-adsorbed dPGA to understand how it provides better support for cell attachment, survival, and growth. High-molecular-weight dPGA (MW 550 kDa) with ∼30% amine functionalization was deposited on silicon wafers from PBS (pH 7.4) solutions to measure the layer thickness and density by ellipsometry and surface roughness and texture by atomic force microscopy (AFM). Colloidal silica (dia ∼ 100 nm) was used as a substrate to measure surface charge (zeta potential), adsorbed amounts by thermal gravimetric analysis (TGA), and molecular mobility by solid-state NMR spectroscopy. We found that the dPGA film properties were dependent on the immersion time in the dPGA coating solution as well as the storage conditions of dPGA solutions. Upon immobilization, dPGA retains a globular but flattened shape. Chain mobility is reduced but the adsorbed dPGA still can be considered a highly flexible polymer that rearranges to present a higher density of positive surface charges as compared to dPGA in solution. Coated surfaces prepared with different deposition times were tested for the capacity to support cells in culture.

Alzheimer’s disease (AD) is a neurodegenerative disorder marked by the accumulation of β-amyloid (Aβ) peptides, which disrupt neuronal homeostasis through their neurotoxic effects. Aβ aggregates interfere with synaptic function by interacting with nicotinic acetylcholine receptors (nAChRs), particularly the α7 subtype, thereby impairing cholinergic signaling, which is crucial for cognition and memory. Pharmacological advancements have identified Positive Allosteric Modulators (PAMs) as promising therapeutic agents to counteract Aβ neurotoxicity. PAMs enhance nAChR activity by binding to allosteric sites, thereby reducing Aβ-induced neurotoxicity without competing with acetylcholine. This study evaluates 3-((6-(phenylethynyl)pyridine-3-yl)oxy)quinuclidine (EQ-04), a novel PAM with high selectivity for the α7 nAChR subtype, demonstrating neuroprotective potential. In vitro analyses using PC-12 cells evaluated the cytotoxic and neuroprotective properties of EQ-04. Cytotoxicity assays confirmed EQ-04’s safety, showing no adverse effects on cell viability across concentrations. EQ-04 significantly enhanced cell viability by 37% at 1 nM against Aβ toxicity and inhibited Aβ aggregation. These findings highlight the potential of EQ-04 as a neuroprotective agent for Alzheimer’s disease (AD) therapy, warranting further investigation into its pharmacokinetics and in vivo efficacy.

Therapies enhancing remyelination offer the exciting prospect of disease-modifying treatments across a number of poorly treated neurological disorders. The class A orphan GPCR, GPR17, is one of the most studied receptors in remyelination; and antagonists of GPR17 have attracted significant attention as potential pro-myelinating medicines. Despite this, the signaling pathways linking GPR17 to remyelination and the molecular mechanisms of action of GPR17 antagonists are not well-defined. In the present study, we characterized GPR17 signaling and inhibition by three chemically distinct GPR17 antagonists: pranlukast, HAMI-3379, and a patent literature antagonist, RWT9996. In HEK293 cells recombinantly expressing GPR17- and BRET-based biosensors, pranlukast preferentially inhibited G protein activation over β-arrestin-2 recruitment, whereas HAMI3379 and RWT9996 equally inhibited all signal transduction tested. Follow-up studies using pharmacological inhibitors and GPR17 antagonists in Oli-neu cells, an immortalized mouse oligodendrocyte precursor cell (OPC) line with endogenous GPR17 expression, corroborated the G protein and β-arrestin coupling profile observed in recombinant cells. Specifically, the generated bias profile suggests that β-arrestin potentiates Gα_q signaling from GPR17, conferring differential regulation of Gα_q signaling by biased GPR17 antagonists. These findings highlight an unappreciated potential for biased signaling in the pharmacology of GPR17 ligands. We anticipate that these insights will help to inform the translation of GPR17-targeted therapies and improve our understanding of GPR17-mediated signaling pathways in governing myelination.

An increasing body of evidence suggests that mitochondrial dysfunction mediated by α-synuclein (α-syn) aggregates plays a key role in the pathogenesis of Parkinson’s disease (PD), leading to intensive research for the discovery and development of compounds with mitoprotective effects. Silymarin (SIL) is a complex mixture of flavonolignans with a wide range of protective effects on mitochondria under stress conditions. Herein, the potency of SIL, in bulk and nano forms, in protecting mitochondria against oxidative damage induced by α-syn aggregates has been investigated. Mitochondria were isolated from rat brain and liver tissues as well as human neuroblastoma SH-SY5Y cells, and damage was evaluated by using a range of biochemical assays. The obtained results show a substantial difference in the response of various mitochondria to oxidative damage induced by α-syn aggregates, with brain mitochondria exhibiting the highest vulnerability. We found that incubation of mitochondria with either bulk or nano forms of SIL before exposure to α-syn aggregates significantly attenuated oxidative damage in a dose-dependent manner. In parallel, α-syn aggregates aged in the presence of bulk or nano forms of SIL considerably lost their capacity to cause mitochondrial damage. While both bulk and nano forms of SIL showed significant mitoprotective effects, SIL nanosheets were much more effective. Possible mechanisms relating to the mitoprotective effects of SIL and the higher efficacy of SIL nanosheets are discussed. The obtained results suggest natural polyphenol-based nanoparticles as an efficient therapeutic approach in relation to amyloid-related diseases, such as PD.

Psychedelic drugs have begun to show therapeutic promise. However, there is a growing research effort focused on creating nonhallucinogenic analogs of these substances. The goal is to develop new treatments for an expanding list of psychiatric and neurodegenerative disorders, while eliminating the complications and costs of treatment engendered by the subjective psychedelic experience. Structure–activity relationships (SAR), particularly for LSD (d-lysergic acid diethylamide), have guided many of these efforts. This perspective examines the historical development and behavioral testing of several simple analogs of LSD’s D-ring, which, while nonhallucinogenic and nontoxic within the context of their testing to date, can block the behavior-disrupting effects of psychedelics administered to rodents. However, these data are quite mature. D-ring analogs of LSD may have therapeutic potential but require further testing to examine binding, plastogenic effects, and potential utility in psychiatry and neuromedicine, and are ripe for reinvestigation with current tools, approaches, and concepts. Further, the SAR data strongly suggest that the incorporation of several changes to the structural elements of the D-ring may enhance the effects of other LSD-related analogs currently undergoing clinical trials.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder in which amyloid-β (Aβ) aggregation plays a pivotal role in its onset and progression. Inhibiting Aβ aggregation is a promising therapeutic strategy; however, its intrinsically disordered and conformationally flexible nature hinders both conventional and computational inhibitor design. Moreover, experimental development of Aβ inhibitors, encompassing molecular design, synthesis, and biological evaluation through repeated assays, is a slow, labor-intensive, and resource-intensive process. Therefore, robust design guidelines and predictive tools are essential for accelerating the discovery of Aβ inhibitors. To overcome these limitations, we developed a machine-learning-based, user-friendly web platform, Amylo-IC₅₀Pred (https://amyloic50pred.vercel.app/), for rapid virtual screening of small molecules targeting Aβ aggregation. The platform integrates two classification models and one regression model, trained on 584 biologically validated compounds. For inhibitor–decoy discrimination, the Random Forest algorithm achieved perfect accuracy (100%). Potency classification into potent, moderately potent, and poor inhibitors was best achieved using Histogram-based Gradient Boosting (81% accuracy). The IC₅₀ regression model, also based on Random Forest, achieved a coefficient of determination (R²) of 0.93, demonstrating strong predictive performance. 2D and 3D key molecular properties such as hydrophobicity, shape and charge distribution, and molecular symmetry were identified as critical contributors to model performance. Importantly, these identified properties provide valuable insights into the molecular features that govern Aβ aggregation inhibition and can serve as a foundation for rational design of potent and selective Aβ aggregation inhibitors. Amylo-IC₅₀Pred thus represents a valuable resource for accelerating AD drug discovery.

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease characterized by memory loss and other cognitive functions. The key hallmarks of AD include extracellular beta-amyloid clumps and intracellular neurofibrillary tau tangles in the neurons. Cholinesterase inhibitors and NMDA-receptor antagonists and their combination are already approved treatments; however, these only give short-term symptom relief. Therefore, new therapeutic techniques and novel drugs are required to combat the century-old AD. This study includes the screening of nine novel small compounds (spiro-indenoquinoxaline-pyrrolidines) via in silico approaches; these compounds have been scrutinized to explore their potential as antiamyloidogenic drugs. Computational tools, including ADMET analysis, molecular docking, and molecular dynamics (MD) simulations, have been used for screening the selected compounds against monomeric peptides of Aβ (Aβ_1–40 and Aβ_1–42) and their oligomeric counterparts, i.e., 6Aβ_9–40 and 6Aβ_1–42. Among the nine molecules screened for this study, ADPR-d reflected the best drug-likeness and negligible toxicity. Further, ADPR-d has the highest binding affinity for all the peptides selected for this study. Additionally, MD simulations of Aβ peptide–ADPR-d complexes confirmed a stable complex formation. In vitro aggregation assay and cell culture studies for Aβ_1–42 also support our in silico findings. The positive findings of the presented study highlight that the ADPR-d molecule may prove to be a potential therapeutic molecule against AD. However, these results would require further in vitro and in vivo analysis before proceeding to clinical settings with these compounds against AD.