ACS Chemical Neuroscience最新文献

G protein-coupled receptors (GPCRs) are among the most prominent druggable targets in the human genome, accounting for approximately 40% of marketed drugs. Despite this, current GPCR-targeted therapies address only about 10% of the GPCRs encoded in the genome. Expanding our knowledge of the remaining "orphan" GPCRs represents a critical frontier in drug discovery. GPR151 emerges as a compelling target due to its distinct expression in the habenula complex, spinal cord neurons, and dorsal root ganglia. This receptor is highly conserved across mammals and possesses orthologs in species such as zebrafish and chickens, underscoring its evolutionarily conserved role in fundamental mammalian processes. Although the precise function of GPR151 remains unknown, it has been strongly implicated in pain modulation and reward-seeking behavior. These attributes position GPR151 as a promising candidate for the development of targeted and specialized pharmacological therapies. This review summarizes the current literature on GPR151, including its discovery, structure, mechanisms, anatomical distribution, and functional roles, while also exploring potential directions for future research.

The interplay between amyloid beta (Aβ) and tau protein is acknowledged as a crucial factor in the progression of Alzheimer's disease (AD), yet the precise molecular mechanisms underlying their interaction remain elusive. In this study, we explore how the key regions within tau, specifically the repeat domains, modulate Aβ aggregation. Through microscale thermophoresis and peptide mapping assays, we identified that tau repeats containing the amyloid motifs VQIINK and VQIVYK directly interact with Aβ(1-42) and Aβ(1-40), targeting the hydrophobic regions of Aβ. Tau repeats were found to inhibit Aβ fibril formation and promote the dissociation of preformed fibrils in vitro. Notably, while disassembling Aβ(1-42) fibrils, tau repeats concurrently stabilized oligomeric forms. These findings provide valuable insights into the complex mechanisms by which tau influences the Aβ pathology, with potential implications for AD progression.

The fibrillation of α-synuclein (α-syn) is a major factor contributing to neuronal damage and is critical in developing synucleopathies-related disorders. Considering this, the discovery of new compounds that can inhibit or modulate α-syn aggregation is a significant area of research. While polyol osmolytes have been shown to reduce α-syn fibrillation, the impact of brain metabolites such as myo-inositol (MI) on α-syn aggregation has not yet been explored. This study is the first to examine the effects of MI on α-syn aggregation, utilizing spectroscopic, microscopic, and cell cytotoxicity assay. Various aggregation assays revealed that MI inhibits the α-syn fibrillation in a dose-dependent manner. Fluorescence microscopy observations suggest that MI inhibits the α-syn fibrillation by forming amorphous aggregates. MTT assay revealed that α-syn aggregates in the presence of different concentrations of MI were not toxic as compared to α-syn fibrils. Thus, the mechanistic insight of inhibition of α-syn fibrillation by MI was explored by employing interaction studies using spectroscopic, calorimetric, and in silico approaches. Surface plasmon resonance and isothermal titration calorimetry suggest that MI-α-syn interacted with significant binding affinity, and the reaction was spontaneous. Molecular docking results depict that MI interacted with the aggregation-prone residues (36-42) at the N-terminal of α-syn, thereby stabilizing the α-syn and preventing the fibril formation. Molecular dynamics simulation results demonstrate the stability of the complex formation of MI with α-syn. This study highlighted the mechanistic insight of MI on preventing the α-syn from forming amyloid fibril, which could be further explored for therapeutic management of synucleopathies-related disorders.

The application of terahertz waves in the field of neurological disease research has gradually attracted attention in recent years. Prior studies have indicated that terahertz waves are capable of alleviating the symptoms of Alzheimer's disease (AD) in mice, yet the underlying relevant mechanisms remain unclear. This study explores the therapeutic potential of terahertz (THz) radiation on AD using a transgenic Caenorhabditis elegans model expressing human tau protein. The nematodes were subjected to 0.1 THz radiation at varying power levels, and its impact on locomotion, tau protein aggregation, and associative learning was evaluated. Results indicate that 0.1 THz irradiation significantly improved the locomotor performance and associative learning of the tau transgenic nematodes, reduced tau aggregation, and increased the expression of SKN-1 and DAF-16. Molecular dynamics simulation revealed that THz waves inhibited the structural stability of tau protofibrils by reducing the protein compactness, altering the secondary structure, reducing hydrogen bond formation, and changing the hydrophobic interaction. Overall, this study demonstrates the potential of low-frequency THz radiation as a nonpharmacological therapy for AD, highlighting its ability to modulate neuronal function and alleviate disease symptoms.

(E)-2-(4-(dimethylamino)styryl)-N,N-dimethylquinolin-6-amine) (THK-5320) is a unique fluorescent compound that recognizes apolipoprotein E (ApoE)-binding amyloid plaques in postmortem human brain sections. To understand the distinctive characteristics of THK-5320 chemically and biologically, its fluorescence properties were investigated, and the association of the fluorescence wavelength with plaque subtypes and amyloid isoforms was explored. Blue plaques visualized with THK-5320 were consistent with those with anti-amyloid-β_1-16/amyloid-β_N3pE-stained antibodies, whereas red plaques visualized with THK-5320 were consistent with those with an ApoE-stained antibody in postmortem brain sections from patients with Alzheimer's disease. In contrast, the amyloid positron emission tomography (PET) tracer PiB and its fluorescent derivative did not show significant signals in ApoE-binding plaques, whereas the signals correlated well with those of amyloid-β_N3pE-positive plaques. Thus, THK-5320 may detect ApoE-binding amyloid plaques that conventional amyloid PET probes cannot detect. Multispectral fluorescence imaging with THK-5320 could be a useful tool to better understand the role of ApoE in amyloid pathology.

Intracerebral hemorrhage (ICH) is a common type of stroke with higher rates of death and neurological dysfunction than ischemic stroke. Based on previous studies, we found that reducing neuronal pyroptosis in the acute phase of ICH improved the neurological dysfunction of mice that suffered from nontraumatic parenchymal hemorrhage. Still, the mechanism must be further explored. In this study, we used ruxolitinib, a selective inhibitor of JAK1/2, to treat CD-1 mice with ICH. We found that inhibition of the JAK1/STAT1 pathway alleviated ICH-induced neuronal pyroptosis and that the activation of caspase-8 was suppressed at the same time. Given that caspase-8 is crosstalk for different types of programmed cell death and its role in the pyroptotic cell death after ICH has not yet been defined, we administered z-IETD-fmk, a selective inhibitor of caspase-8, to treat mice with ICH. We found that the downregulation of caspase-8 reversed ICH-induced neuronal pyroptosis and improved motor and cognitive functions of mice after ICH. Our results show that the JAK1/STAT1/caspase-8 axis is a critical mediator of neuronal pyroptosis in ICH. Inhibiting this axis improved neurological outcomes of mice with ICH, and we propose ruxolitinib as a potential therapeutic approach for post-ICH treatment.

Disease progression in synucleinopathies is associated with the formation of seeding-competent α-synuclein (αSyn) aggregates. After spreading and cellular uptake, the αSyn seeds propagate in a prion-like mechanism by inducing the conversion of natively folded αSyn into pathogenic aggregates. Here we show that the soluble intrinsically disordered N-terminal domain of the cellular prion protein (N1-PrP) modulates fibrillization of αSyn to form off-pathway aggregates that lack seeding activity in cells. N1-PrP does not interact with soluble αSyn. However, during the aggregation of αSyn in vitro, N1-PrP is recruited and incorporated. As a result, amorphous coaggregates are formed instead of seeding-competent αSyn fibrils. Similarly, in the cytosol of neuronal cells N-PrP specifically interacts with αSyn during the prion-like propagation of pathogenic αSyn seeds. These findings identify a unique neuroprotective activity of the soluble N-terminal domain of the prion protein by promoting off-pathway reactions in amyloid seed formation.

Indocyanine green (ICG) is an amphiphilic, near-infrared, FDA-approved fluorescent dye with established voltage sensitivity in biomembranes, making it a promising candidate for voltage sensing and imaging, particularly in neurons where action potentials drive dynamic changes in membrane potential. In this study we investigate the molecular determinants of ICG's voltage sensitivity in polarized lipid membranes. Combining molecular simulations with electronic structure calculations, we analyze how the membrane environment modulates ICG's photoabsorption, a step preceding fluorescent emission. Our findings reveal that the optical response of the dye to the transmembrane potential is indirect: the transmembrane potential not only influences the dye's localization within the membrane but also affects its immediate charge environment, ultimately driving the electrochromic spectral shift. A key feature of our approach is the inclusion of the inhomogeneous charge environment arising from membrane polarization in the optical response calculations. We show that accurately capturing the dye's photoabsorption response to a change in the membrane voltage requires a detailed atomistic description of the dye-lipid Coulomb interactions, beyond the scope of homogeneous field approximations or continuum solvation models.

Neuropeptides are vital signaling molecules involved in neural communication, hormonal regulation, and stress response across diverse taxa. Despite their critical roles, neuropeptide research remains challenging due to their low abundance, complex post-translational modifications (PTMs), and dynamic expression patterns. Mass spectrometry (MS)-based neuropeptidomics has revolutionized peptide identification and quantification, enabling the high-throughput characterization of neuropeptides and their PTMs. However, the complexity of vertebrate neural networks poses significant challenges for functional studies. Invertebrate models, such as Cancer borealis, Drosophila melanogaster, and Caenorhabditis elegans, offer simplified neural circuits, well-characterized systems, and experimental tools for elucidating the functional roles of neuropeptides. These models have revealed conserved neuropeptide families, including allatostatins, RFamides, and tachykinin-related peptides, whose vertebrate homologues regulate analogous physiological functions. Recent advancements in MS techniques, including ion mobility spectrometry and MALDI MS imaging, have further enhanced the spatial and temporal resolution of neuropeptide analysis, allowing for insights into peptide signaling systems. Invertebrate neuropeptide research not only expands our understanding of conserved neuropeptide functions but also informs translational applications including the development of peptide-based therapeutics. This review highlights the utility of invertebrate models in neuropeptide discovery, emphasizing their contributions to uncovering fundamental biological principles and their relevance to vertebrate systems.

Neuroinflammation is a key factor in age-related cognitive decline and memory impairment. UAS03, a potent synthetic analogue of Urolithin-A, has demonstrated anti-inflammatory and antioxidant properties. This investigation examined the neuroprotective effect of UAS03 on lipopolysaccharide (LPS) induced neuroinflammation, and its associated cognitive impairments, memory deficits, and depression-like behaviors. Intracerebroventricular administration of LPS (12 μg/kg) was performed to induce neuroinflammation in mice, followed by a 7 day treatment with UAS03 at 10 and 30 mg/kg doses. Mice were evaluated for depressive and anxiety-like behavior, spatial memory, and learning functions using a series of neurobehavioral test paradigms. Histopathological and molecular analyses were conducted using hematoxylin-eosin and cresyl violet staining, immunohistochemistry, ELISA, and Western blotting techniques. We have found that, UAS03 significantly enhanced cognitive and memory functions impaired by LPS while concurrently reducing depressive symptoms. Furthermore, the compound attenuated neuronal damage and decreased the expression of IBA-1 and GFAP in hippocampal region. Through the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, UAS03 effectively mitigated markers of oxidative stress and reduced levels of pro-inflammatory factors, including IL-1β, TNF-α, and COX-2. Cumulatively, this study provides compelling evidence that UAS03 exerts neuroprotective effects by regulating essential pathways involved in anti-inflammatory and neuroprotective mechanisms, suggesting its potential as a preventative measure against age-related cognitive decline and memory impairments associated with neuroinflammation.