ACS Chemical Neuroscience最新文献

{"title":"Interplay of Endoplasmic Reticulum Stress, Inflammation, Apoptosis, and Oxidative Stress in Corticosteroid-Induced Anxiety and Depression: Exploring Therapeutic Potential of Hydrogen Sulfide and Sertraline","authors":"May A. Azzam,&nbsp;Asmaa A. ElMonier*,&nbsp;Enas S. Gad and Mai A. Abd-Elmawla,&nbsp;","doi":"10.1021/acschemneuro.5c0005710.1021/acschemneuro.5c00057","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00057https://doi.org/10.1021/acschemneuro.5c00057","url":null,"abstract":"<p >Prolonged exposure to corticosteroids (CORTs) triggers depression and anxiety symptoms either endogenously or exogenously via stimulating endoplasmic reticulum stress (ERS). The study assessed the therapeutic implications of hydrogen sulfide (H₂S) versus sertraline (SERT) in alleviating anxiety and depression induced by CORTs through the modulation of ERS and its inflammatory, oxidative, and apoptotic consequences. Rats were subdivided into four groups: control, CORT (20 mg/kg), NaHS (100 μmol/kg), and SERT (10 mg/kg) for 21 days. Behavioral and histological examinations of the cerebral cortex were performed. The levels of CHOP, GADD34, EIF2AK3, GRP78, caspase 3, and miR-146a were analyzed using qRT-PCR. The levels of CORTs, serotonin, BDNF, TNF-α, BCL2, NRF2, and ATF4 were measured using ELISA, whereas those of IL-1β and BAX were measured using immunohistochemical techniques. Total and phosphorylated PERK were assessed via western blotting, whereas GSH and MDA were assessed via a colorimetric assay. In the present study, CORTs upregulated the gene expression of CHOP, GADD34, EIF2AK3, GRP78, and Caspase 3, whereas it downregulated that of miR-146a. The levels of serotonin, BDNF, BCL2, GSH, and NRF2 were decreased, whereas those of ATF4, TNF-α, IL-1β, BAX, and MDA were elevated. On the contrary, NaHS and SERT reversed all the above-mentioned changes. H₂S shows promise in counteracting anxiety and depression symptoms induced by CORTs by targeting ERS cascades, mitigating inflammation, oxidative insults, and apoptosis in the cerebral cortex. H₂S elicits neuroprotective effects by targeting the miR-146a-3p/GRP78/CHOP/PERK/ATF4/GADD34 signaling pathway and regulating apoptotic markers BAX/BCL2 and inflammatory markers TNF-α and/IL-1β. Compared with SERT, H₂S exhibited superior anxiolytic and antidepressive effects.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 7","pages":"1361–1376 1361–1376"},"PeriodicalIF":4.1,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143746127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of the Parkinson's Disease-Related Protein DJ-1 by Endogenous Neurotoxins of the 1,2,3,4-Tetrahydroisoquinoline Family.","authors":"Catherine Laurent, Gabrielle Poncet, Tristan Herskovits, Rodolphe Alves de Sousa, Laurent Le Corre, Mohammed Al-Azzani, Annekatrin Koenig, Serge Birman, Tiago Fleming Outeiro, Daniel Mansuy, Julien Dairou","doi":"10.1021/acschemneuro.4c00559","DOIUrl":"10.1021/acschemneuro.4c00559","url":null,"abstract":"<p><p>The protein DJ-1 appears to play a protective role in the development of Parkinson's disease (PD). Here, we show that endogenous neurotoxins of the 1,2,3,4-tetrahydroisoquinoline family (TIQs), formed upon reaction of various aldehydes such as methylglyoxal (MGO) with the neurotransmitter dopamine, act as irreversible inhibitors of the esterase activity of human DJ-1, with IC50 values between 15 and 57 μM. The presence of a catechol function appears to be essential for these inhibitory effects, which may be at the origin of the oxidation of cysteine 106, a crucial residue in the DJ-1 active site, thereby leading to DJ-1 inhibition. We also show that these endogenous neurotoxins inhibit the protective effects of DJ-1 against glycated guanosine diphosphate (GDP) formation and against alpha-synuclein (aSyn) aggregation induced by MGO. In total, the observed inhibition of DJ-1 by these endogenous neurotoxins may contribute to their damaging effects on the nervous system and, should be taken into account in therapeutic strategies for PD and related disorders.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"1034-1042"},"PeriodicalIF":4.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143497477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acridine Benzimidazolium Derivatives Induced Protective Microglia Polarization and <i>In Silico</i> TDP-43 Interaction─Potential Implications for Amyotrophic Lateral Sclerosis.","authors":"Neeraja Revi, Muneshwar Nandeshwar, Dinesh Harijan, Sri Amruthaa Sankaranarayanan, Meet Joshi, Ganesan Prabusankar, Aravind Kumar Rengan","doi":"10.1021/acschemneuro.4c00791","DOIUrl":"10.1021/acschemneuro.4c00791","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Abnormal protein aggregation and associated neuronal-glial cell cytotoxicity lead to a plethora of neurodegenerative disorders. Most of the earlier investigations on understanding neurodegenerative disease progression and cure focused on neuronal damage and restoration potential. With increased evidence on the role of glial cells like microglia and astrocytes in mediating these disorders, more studies are dedicated to understanding the role of inflammatory responses mediated by glial cells and how they lead to neuroinflammation. Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder caused by TDP-43 aggregation that affects motor neurons. Pro-inflammatory microglia are considered to aggravate the disorder condition. In the current study, a previously reported molecule with TDP-43 inhibition, 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(carboxymethyl)imidazol-3-ium) dibromide salt (&lt;b&gt;AIM4&lt;/b&gt;), is analyzed for its microglia polarization properties along with two other derivatives, 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(2-ethoxy-2-oxoethyl)benzimidazol-3-ium) dibromide salt (&lt;b&gt;ABE&lt;/b&gt;) and 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(carboxymethyl)benzoimidazol-3-ium) dibromide salt (&lt;b&gt;ABA&lt;/b&gt;). The 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(2-ethoxy-2-oxoethyl)benzimidazol-3-ium) dibromide salt (&lt;b&gt;ABE&lt;/b&gt;) and 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(carboxymethyl) benzimidazol-3-ium) dibromide salt (&lt;b&gt;ABA&lt;/b&gt;) display the increased ability to maintain microglial cells to anti-inflammatory state and TDP-43 binding as compared to 3,3'-(acridine-4,5-diylbis(methylene)) bis(carboxymethyl)imidazolium dibromide salt (&lt;b&gt;AIM4&lt;/b&gt;). This was confirmed from total nitrite levels, mitochondria membrane potential analysis, and molecular docking studies. The selected pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) displayed decreased levels, and anti-inflammatory cytokines IL-4 and IL-10 displayed increased levels, however not very significantly, upon treatment with all acridine derivatives. The compounds were investigated on lipopolysaccharides (LPS)-triggered mouse microglial cells and &lt;i&gt;Danio rerio&lt;/i&gt; embryos displaying no significant cytotoxicity and physiological changes (cardiac rhythm), respectively. In molecular docking studies, alanine at 315 mutated to glutamate of TDP-43 directly interacts with &lt;b&gt;AIM4&lt;/b&gt;. However, π-σ interactions of the aromatic backbone of acridine in &lt;b&gt;ABE&lt;/b&gt; and &lt;b&gt;ABA&lt;/b&gt; with 313 phenylalanine of TDP-43 along with hydrogen bonds formed between 309, 310 glycine amino acids and imidazolium bromide side chains rendered a stronger binding of these acridine derivatives with the protein potentially inhibiting fibrillation. &lt;b&gt;Conclusion: ABA&lt;/b&gt;, &lt;b&gt;ABE&lt;/b&gt;, and &lt;b&gt;AIM4&lt;/b&gt; maintain microglia in an anti-inflammatory state. However, more studies are required to understand its interaction with TDP-43 and the mechanism of its anti-inflammatory n","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"1103-1116"},"PeriodicalIF":4.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cytotoxicity of Amyloid β1-42 Fibrils to Brain Immune Cells.","authors":"Mikhail Matveyenka, Mikhail Sholukh, Dmitry Kurouski","doi":"10.1021/acschemneuro.4c00835","DOIUrl":"10.1021/acschemneuro.4c00835","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a progressive pathology that is linked to abrupt aggregation of amyloid β_1-42 (Aβ_1-42) peptide in the central nervous system. Aβ_1-42 aggregation yields amyloid oligomers and fibrils, toxic protein aggregates that cause progressive neuronal degeneration in the frontal lobe of the brain. Although neurons remain the focus of AD for decades, a growing body of evidence suggests that the degeneration of immune cells in the brain can be the major cause of AD. However, the extent to which Aβ_1-42 aggregates are toxic to the major classes of immune cells in the brain remains unclear. In the current study, we examine the cytotoxic effects of Aβ_1-42 fibrils on macrophages, dendritic cells, and microglia. These cells play vitally important roles in development and homeostasis of the central nervous system. We found that Aβ_1-42 fibrils caused calcium release and enhanced levels of reactive oxygen species in macrophages, dendritic cells, and microglia as well as neurons. We also investigated the extent to which the lysozymes of these immune cells could alter the aggregation properties of Aβ_1-42. Our results showed that lysosomes extracted from macrophages, dendritic cells, and microglia drastically accelerated Aβ_1-42 aggregation as well as altered cytotoxicity of these protein aggregates. These results indicate that impairment of immune cells in the brain can be a critically important aspect of neurodegenerative processes that are taking place upon the onset of AD.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"1144-1149"},"PeriodicalIF":4.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11926782/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Monoamine Oxidase Inhibitors Present in Tobacco Modulate Dopamine Balance Via the Dopamine Transporter.","authors":"Gabriella Saro, Stephanie Johne, Diogo A R S Latino, Fabian Moine, Marco van der Toorn, Carole Mathis, Emilija Veljkovic","doi":"10.1021/acschemneuro.4c00789","DOIUrl":"10.1021/acschemneuro.4c00789","url":null,"abstract":"<p><p>It has been reported that nicotine affects brain dopamine homeostasis. By binding to nicotinic acetylcholine receptors, including those expressed by dopaminergic neurons of the ventral tegmental area, nicotine stimulates dopamine release and signaling. Dopamine is taken up from the synaptic cleft by the dopamine transporter (DAT) into presynaptic neurons, where it is degraded by monoamine oxidase (MAO). Besides nicotine, other tobacco compounds play a role in dopamine modulation. To better understand the biological effects of nicotine and other tobacco compounds on dopamine regulation, we selected a group of tobacco compounds based on their potential affinity to bind human MAO-A and MAO-B enzymes using an <i>in silico</i> approach. Subsequently, we tested the putative compounds in an enzymatic assay to verify their ability to inhibit human MAO-A or MAO-B. The positive hits were harman, norharman, harmaline, and 1-ethyl-β-carboline. While harman and norharman have been extensively studied, both harmaline and 1-ethyl-β-carboline have not been described in the context of tobacco and MAO inhibition before. We investigated DAT activity in an overexpressing cell line and dopamine release and uptake in rat striatal synaptosomes. We clearly demonstrate that tested MAO-A inhibitors (MAO-AIs) significantly attenuated human DAT activity and consequent dopamine uptake, establishing a functional connection between MAOIs and dopamine uptake via DAT. Interestingly, the tested MAO-AIs elicited pronounced dopamine release in crude synaptosomal preparations. In summary, this <i>in vitro</i> study demonstrates that tested MAO-AIs found in cigarette smoke not only reduce MAO activity but also strongly impact dopamine homeostatic mechanisms via DAT. Further <i>in vivo</i> investigations would advance our understanding of the underlying mechanisms of dopamine regulation and homeostasis.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"1117-1131"},"PeriodicalIF":4.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11926787/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential Effects of Aβ Peptides on the Plasmin-Dependent Degradation of ApoE3 and ApoE4.","authors":"Merc M Kemeh, Anthony J Furnelli, Noel D Lazo","doi":"10.1021/acschemneuro.5c00065","DOIUrl":"10.1021/acschemneuro.5c00065","url":null,"abstract":"<p><p>The <i>ApoE4</i> allele of apolipoprotein E (ApoE4) is the strongest hereditary predisposition to Alzheimer's disease, even though ApoE4 only differs from the more common ApoE3 by a single amino acid substitution. Previous studies have shown that ApoE4 is more susceptible to proteolytic degradation than ApoE3. This is an important finding because of ApoE's role in cholesterol homeostasis and lipid transport in the brain. The molecular determinants of the increased susceptibility of ApoE4 to proteolysis are unknown. Here, we apply a combination of spectrometric and spectroscopic methods to show that amyloid-β (Aβ) peptides, including Aβ(1-40) and Aβ(pyroE3-42), differentially modulate the plasmin-dependent degradation of ApoE3 and ApoE4. In particular, our data reveal that while the Aβ peptides do not affect the proteolysis of ApoE3, the peptides enhance the degradation of ApoE4 significantly. Overall, this work motivates therapeutic development that targets the Aβ-induced dysregulation of ApoE4 homeostasis in individuals carrying the <i>ApoE4</i> allele.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"1227-1237"},"PeriodicalIF":4.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>SCN8A</i> Epileptic Encephalopathy Mutation Displays a Loss-of-Function Phenotype and Distinct Insensitivity to Valproate.","authors":"Yudan Zhu, Guangfei Wang, Kaixuan Wang, Meng Sun, Lu Zhao, Yunqing Zeng, Cuina Yan, Yonghua Ji, Yangbo Hou, Zhiping Li, Jie Tao","doi":"10.1021/acschemneuro.4c00828","DOIUrl":"10.1021/acschemneuro.4c00828","url":null,"abstract":"<p><p>Voltage-gated sodium channels are the main targets of antiepileptic drugs, such as sodium valproate (VPA). Single nucleotide polymorphisms (SNPs) in the Nav1.6 isoform (<i>SCN8A</i>) have been reported to be closely associated with motor dysfunction in pediatric akathisia epileptica. In this study, we conducted a genetic screening of pediatric patients with seizures treated solely with VPA and identified two novel missense mutations of <i>SCN8A</i> (A1534V and Q1853H). Electrophysiological results revealed that the peak currents of the A1534V variant were smaller compared to that of the wild-type (WT) channel. The A1534V variant also caused a positive shift in the <i>I</i>-<i>V</i> curve, indicating a change in the voltage dependence of activation compared to the WT channels. In contrast, VPA induced a significant negative shift in the inactivation of both WT and A1534V mutant. However, the inhibition of currents by VPA was weaker in the A1534V variant than in WT. Furthermore, the recovery time constant of the A1534V variant was shorter than that of WT when treated with VPA. Regrettably, although the Q1853H variant can be expressed in HEK293T cells, the detected current is too small (approximately 50 pA). In conclusion, our results suggest that the A1534V mutation is a novel loss-of-function variant that exhibits moderate insensitivity to VPA. These results underscore the importance of Nav1.6 as a key target in epilepsy and highlight the necessity of analyzing its role in the pathological process.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"1132-1143"},"PeriodicalIF":4.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrating Rapid Evaporative Ionization Mass Spectrometry Classification with Matrix-Assisted Laser Desorption Ionization Mass Spectrometry Imaging and Liquid Chromatography-Tandem Mass Spectrometry to Unveil Glioblastoma Overall Survival Prediction.","authors":"Tim F E Hendriks, Angeliki Birmpili, Steven de Vleeschouwer, Ron M A Heeren, Eva Cuypers","doi":"10.1021/acschemneuro.4c00463","DOIUrl":"10.1021/acschemneuro.4c00463","url":null,"abstract":"<p><p>Glioblastoma multiforme (GBM) is a highly aggressive brain cancer with a median survival of 15 months. Despite advancements in conventional treatment approaches such as surgery and chemotherapy, the prognosis remains poor. This study investigates the use of rapid evaporative ionization mass spectrometry (REIMS) for real-time overall survival time classification of GBM samples and uses matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) to compare lipidomic differences within GBM tumors. A total of 45 GBM biopsies were analyzed to develop a survival prediction model for IDH-wild type GBM. REIMS patterns from 28 patients were classified with a 97.7% correct classification rate, identifying key discriminators between short-term (0-12 months) and prolonged (>12 months) survivors. Cross-validation with additional samples showed that the model correctly classified short-term and prolonged survival with 66.7 and 69.4% accuracy, respectively. MALDI-MSI was performed to confirm the discriminators derived from REIMS data. Results indicated 42 and 33 discriminating features for short-term and prolonged survival, respectively. Proteomic profiling was performed by isolating tumor regions via laser-capture microdissection (LMD) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Subsequently, 1387 proteins were identified, of which 79 were significantly altered. In conclusion, this study shows that REIMS rapidly predicts glioblastoma survival times based on lipidomic profiles during electrosurgical dissection. MALDI-MSI confirmed that these differences were specific to the tumor region in the glioblastoma sections. LMD-guided LC-MS/MS-based proteomics revealed significantly altered pathways between short-term and prolonged survival. This research, including the comprehensive predictive survival model for GBM, could guide tumor resection surgeries based on accurate real-time tumor tissue identification as well as provide insights into overall survival mechanisms, possibly related to therapy response.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"1021-1033"},"PeriodicalIF":4.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11926789/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143497478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Determinants for Substoichiometric Inhibition of IAPP and Aβ Amyloid Aggregations by Bri2 BRICHOS.","authors":"Zhenzhen Zhang, Gangtong Huang, Shivani Gupta, Emma Sargent, Huayuan Tang, Feng Ding","doi":"10.1021/acschemneuro.4c00839","DOIUrl":"10.1021/acschemneuro.4c00839","url":null,"abstract":"<p><p>Bri2 BRICHOS, a folded domain of the transmembrane protein Bri2 expressed in both the brain and pancreas, is an experimentally known substoichiometric inhibitor of amyloid aggregation. The molecular chaperone effectively delays fibrillization at low molar ratios for both β-amyloid (Aβ) in Alzheimer's disease (AD) and islet amyloid polypeptide (IAPP) in type 2 diabetes (T2D). While discovering effective antiamyloid inhibitors that work at low doses is an appealing strategy to mitigate amyloid toxicity, the molecular mechanism underlying the broad and efficient antiamyloid activity of Bri2 BRICHOS remains unknown. Here, we computationally demonstrated that Bri2 BRICHOS exhibits a stronger binding affinity to fibril seeds than to monomers using atomistic discrete molecular dynamic simulations. By competing with monomers to bind the active elongation sites on newly nucleated, weakly populated fibril seeds, a small amount of Bri2 BRICHOS could block rapid fibril growth via monomer addition. The experimentally observed differential inhibition efficiency against IAPP and Aβ aggregation was found to depend on the relative fibril-binding affinities of the inhibitor compared to those of self-seeding monomers. Our computationally derived determinants for substoichiometric inhibition against amyloid aggregation by Bri2 BRICHOS may inform the future design of potent antiamyloid therapies for AD, T2D, and other amyloid diseases.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"1150-1160"},"PeriodicalIF":4.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11922669/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dysregulated Neurotransmission and the Role of Viruses in Alzheimer's Disease.","authors":"Katherine Bovis, Martha Davies-Branch, Philip J R Day","doi":"10.1021/acschemneuro.4c00763","DOIUrl":"10.1021/acschemneuro.4c00763","url":null,"abstract":"<p><p>The causes of neurodegeneration remain elusive. There is growing evidence linking viral infection to dysregulated neurotransmission as a causative factor in Alzheimer's disease. Studies suggest that viral infection may result in dysregulated glutamatergic and l-arginine/NO neurotransmission that can initiate neurodegeneration and neuroinflammation within AD. This involves viral infection (HIV-1/HSV-1) altering glutamate biosynthesis and receptor activation resulting in excessive influxes of glutamate and subsequent dysregulation of Ca²⁺ influx that all contribute to reduced dendrite growth and tau phosphorylation. For l-arginine/NO neurotransmission, the mechanism derives from the \"protective\" antiviral mechanisms of NO that correlate with pathologies such as β-amyloid peptide accumulation and functional degeneration of hippocampal neurons, respectively. More research is required to underpin the direct mechanisms that viruses might impact to induce specific pathologies.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"982-987"},"PeriodicalIF":4.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11926781/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}