ACS Chemical Neuroscience最新文献

{"title":"Discovery of VU0467319: an M₁ Positive Allosteric Modulator Candidate That Advanced into Clinical Trials.","authors":"Michael S Poslunsey, Michael R Wood, Changho Han, Shaun R Stauffer, Joseph D Panarese, Bruce J Melancon, Julie L Engers, Jonathan W Dickerson, Weimin Peng, Meredith J Noetzel, Hyekyung P Cho, Alice L Rodriguez, Corey R Hopkins, Ryan Morrison, Rachel D Crouch, Thomas M Bridges, Anna L Blobaum, Olivier Boutaud, J Scott Daniels, Michael J Kates, Arlindo Castelhano, Jerri M Rook, Colleen M Niswender, Carrie K Jones, P Jeffrey Conn, Craig W Lindsley","doi":"10.1021/acschemneuro.4c00769","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00769","url":null,"abstract":"<p><p>Herein we detail the <i>first disclosure</i> of VU0467319 (VU319), an M₁ Positive Allosteric Modulator (PAM) clinical candidate that successfully completed a Phase I Single Ascending Dose (SAD) clinical trial. VU319 (<b>16</b>) is a moderately potent M₁ PAM (M₁ PAM EC₅₀ = 492 nM ± 2.9 nM, 71.3 ± 9.9% ACh Max), with minimal M₁ agonism (EC₅₀ > 30 μM), that displayed high CNS penetration (<i>K</i>_p<i>s</i> > 0.67 and <i>K</i>_p,uu<i>s</i> > 0.9) and multispecies pharmacokinetics permissive of further development. Based on robust efficacy in multiple preclinical models of cognition, an ancillary pharmacology profile devoid of appreciable off-target activities, and a lack of cholinergic adverse effects (AEs) in rats, dogs and nonhuman primates, VU319 advanced into IND-enabling studies. After completing 4-week rat and dog GLP toxicology without AEs, including absence of cholinergic effects, the first in human Phase I SAD clinical trial of VU319 (NCT03220295) was performed at Vanderbilt, where a similar lack of adverse effects, including absence of cholinergic effects was noted. Moreover, signals of target engagement were seen at the highest dose tested. Thus, VU319 demonstrated the feasibility of achieving selective targeting of central M₁ muscarinic receptors without eliciting cholinergic AEs that have plagued other drugs targeting CNS cholinergic neurotransmission.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805524","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":"Guanidine Derivative ADS1017, a Potent Histamine H3 Receptor Antagonist with Promising Analgesic Activity and Satisfactory Safety Profile","authors":"Tadeusz Karcz*,&nbsp;Katarzyna Szczepańska,&nbsp;Szczepan Mogilski,&nbsp;Aleksandra Moroz,&nbsp;Agnieszka Olejarz-Maciej,&nbsp;Laura J. Humphrys,&nbsp;Steffen Pockes,&nbsp;Agata Siwek,&nbsp;Krzysztof Dubiel,&nbsp;Marek Staszewski,&nbsp;Thierry Calmels,&nbsp;Krzysztof Waczyński and Katarzyna Kieć-Kononowicz,&nbsp;","doi":"10.1021/acschemneuro.4c0048010.1021/acschemneuro.4c00480","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00480https://doi.org/10.1021/acschemneuro.4c00480","url":null,"abstract":"<p >In this study, we selected 12 guanidine derivatives from the previously described ligand library and determined their affinity at histamine H₃ and H₄ receptors (H₃R and H₄R, respectively). Moreover, we also checked their intrinsic activity toward H₃R and muscarinic M₁, M₂, and M₄ receptors (M₁R, M₂R, and M₄R, respectively). Since ADS1017 has been proved to be the most selective and highly potent H₃ antagonist in our series, we chose it as the lead structure for further biological evaluation. To extend the study of its <i>in vivo</i> efficacy, we proposed an alternative synthetic route that resulted in an increased yield. Interestingly, ADS1017 showed a broad spectrum of analgesic activity in both nociceptive and neuropathic pain models. Finally, as a result of comprehensive analysis of its off-target activity and ADMETox parameters, we confirmed the moderate selectivity of ADS1017 and its promising drug-like properties.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"15 24","pages":"4441–4457 4441–4457"},"PeriodicalIF":4.1,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142842841","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":"Neuroreceptor Mapping in 2024","authors":"Ramya Tokala,&nbsp; and ,&nbsp;Jacob M. Hooker*,&nbsp;","doi":"10.1021/acschemneuro.4c0075410.1021/acschemneuro.4c00754","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00754https://doi.org/10.1021/acschemneuro.4c00754","url":null,"abstract":"<p >Neuroreceptor mapping provides insights into neurotransmitter changes and receptor dynamics that improve the understanding of brain functions. This Viewpoint highlights the advancements in the development of novel radiotracers (imaging tools) and quantification of receptor dynamics based on presentations from the <i>XIV International Symposium on Functional Neuroreceptor Mapping (NRM) of the Living Brain</i>, 2024. The Viewpoint also emphasizes the applications of neuroreceptor mapping in clinical research and the latest technologies for imaging the brain with positron emission tomography (PET). The goal of the Viewpoint is to highlight an important community of researchers within the field of chemical neuroscience.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"15 24","pages":"4348–4351 4348–4351"},"PeriodicalIF":4.1,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142842838","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":"Novel Perspective on Sevoflurane-Induced Cognitive Dysfunction: Implications of Neuronal SIRPα and Microglial Synaptic Remodeling","authors":"Wei Du,&nbsp;Xiaomin Zhang,&nbsp;Songze Li and Xin Xie*,&nbsp;","doi":"10.1021/acschemneuro.4c0048510.1021/acschemneuro.4c00485","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00485https://doi.org/10.1021/acschemneuro.4c00485","url":null,"abstract":"<p >This study aims to investigate the role of neuronal SIRPα and microglial synaptic remodeling in sevoflurane-induced cognitive dysfunction in newborn mice. Newborn mice were exposed to sevoflurane, followed by behavioral assessments and single-cell transcriptome sequencing of cortical cells. Lentivirus-mediated overexpression of neuronal SIRPα and assessment of the microglial morphology and synaptic function were conducted. Sevoflurane exposure resulted in social cognitive impairments without affecting motor coordination. Transcriptomic analysis revealed no significant changes in cortical microglial cells or neurons. However, sevoflurane inhibited nonsynaptic synapse modification by microglia. Overexpression of neuronal SIRPα enhanced microglial function, promoted neuron development, and ameliorated cognitive impairments. SCENIC analysis identified a correlation between IRF8 and SIRPα expression. This study sheds light on the involvement of neuronal SIRPα and microglial synaptic remodeling in sevoflurane-induced cognitive dysfunction. Understanding these mechanisms offers new avenues for exploring cognitive impairment pathways and potential therapeutic targets.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"15 24","pages":"4500–4516 4500–4516"},"PeriodicalIF":4.1,"publicationDate":"2024-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142850539","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":"Structural Analysis of Variants of the Ferritin Light Chain Protein and Its Relationship with Neuroferritinopathy","authors":"Madelin Gómez Hernández*,&nbsp;Alejandro Soto-Ospina,&nbsp;Cristian Andrés Osorio and Andrés Villegas-Lanau,&nbsp;","doi":"10.1021/acschemneuro.4c0040010.1021/acschemneuro.4c00400","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00400https://doi.org/10.1021/acschemneuro.4c00400","url":null,"abstract":"<p >Ferritin is a highly conserved spherical protein that stores iron and possesses triple and quadruple symmetry input ports. Additionally, it is composed of light chains that can be affected by post-translational mutations, reducing the iron storage capacity in the brain and leading to neuroferritinopathy, which is a rare disease with limited bioinformatics data. In this study, we analyzed the biochemical mechanism of different ferritin mutations reported in the literature, through the characterization and determination of the <i>in silico</i> structural model by searching databases, implementing bioinformatics programs such as Jalview, NetNGlyc 1.0, NetOGlyc 3.1, and three-dimensional structure predictors with machine learning such as Alphafold, demonstrating the generation of hairpin and steric hindrances that hinder the aggregation of subunits and changes in the size and arrangement of quadruple and triple entry holes of the A96T mutation compared to the wild-type protein, since in the quadruple entry hole, a decrease in area is observed compared to the wild-type protein and the triple entry hole has a decrease in distance measurements of 6.504 Å. This possibly affects the functionality of the protein, thus releasing high concentrations of iron in the brain and causing neurodegeneration.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"15 24","pages":"4402–4417 4402–4417"},"PeriodicalIF":4.1,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142850269","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":"Serotonin 1A Receptors Modulate Serotonin 2A Receptor-Mediated Behavioral Effects of 5-Methoxy-N,N-dimethyltryptamine Analogs in Mice","authors":"Grant C. Glatfelter*,&nbsp;Allison A. Clark,&nbsp;Natalie G. Cavalco,&nbsp;Antonio Landavazo,&nbsp;John S. Partilla,&nbsp;Marilyn Naeem,&nbsp;James A. Golen,&nbsp;Andrew R. Chadeayne,&nbsp;David R. Manke,&nbsp;Bruce E. Blough,&nbsp;John D. McCorvy and Michael H. Baumann,&nbsp;","doi":"10.1021/acschemneuro.4c0051310.1021/acschemneuro.4c00513","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00513https://doi.org/10.1021/acschemneuro.4c00513","url":null,"abstract":"<p >5-methoxy-<i>N</i>,<i>N</i>-dimethyltrytpamine (5-MeO-DMT) analogs are used as recreational drugs, but they are also being developed as potential medicines, warranting further investigation into their pharmacology. Here, we investigated the neuropharmacology of 5-MeO-DMT and several of its <i>N</i>-alkyl, <i>N</i>-allyl, and 2-methyl analogs, with three major aims: 1) to determine in vitro receptor profiles for the compounds, 2) to characterize in vitro functional activities at serotonin (5-HT) 2A receptors (5-HT_2A) and 1A receptors (5-HT_1A), and 3) to examine the influence of 5-HT_1A on 5-HT_2A-mediated psychedelic-like effects in the mouse head twitch response (HTR) model. In vitro receptor binding and functional assays showed that all 5-MeO-DMT analogs bind with high affinity and activate multiple targets (e.g., 5-HT receptor subtypes, alpha adrenergic receptors), including potent effects at 5-HT_2A and 5-HT_1A. In C57Bl/6J mice, subcutaneous injection of the analogs induced HTRs with varying potencies (ED₅₀ range = 0.2–1.8 mg/kg) and maximal effects (<i>E</i>_max range = 20–60 HTRs/30 min), while inducing hypothermia and hypolocomotion at higher doses (ED₅₀ range = 3.2–20.6 mg/kg). 5-HT_2A antagonist pretreatment blocked drug-induced HTRs, whereas 5-HT_1A antagonist pretreatment enhanced HTRs. In general, <i>N</i>,<i>N</i>-dialkyl and <i>N</i>-isopropyl derivatives displayed HTR activity, while the <i>N</i>-methyl, <i>N</i>-ethyl, and 2-methyl analogs did not. Importantly, blockade of 5-HT_1A unmasked latent HTR activity for the <i>N</i>-ethyl analog and markedly increased maximal responses for other HTR-active compounds (40–90 HTRs/30 min), supporting the notion that 5-HT_1A agonist activity can dampen 5-HT_2A-mediated HTRs. Suppression of 5-HT_2A-mediated HTRs by 5-HT_1A only occurred after high 5-MeO-DMT doses, suggesting involvement of other receptors in modulating psychedelic-like effects. Overall, our findings provide key information about the receptor target profiles for 5-MeO-DMT analogs, the structure–activity relationships for inducing psychedelic-like effects, and the critical role of 5-HT_1A agonism in modulating acute psychoactive effects of 5-HT_2A agonists.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"15 24","pages":"4458–4477 4458–4477"},"PeriodicalIF":4.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142850522","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":"Stereospecific Properties and Intracellular Transport of Novel Intrinsically Fluorescent Neurosteroids.","authors":"Vibeke Akkerman, Peter Reinholdt, Rasmus Schnoor-Madsen, Line Lauritsen, Jad Bader, Minxing Qian, Yuanjiang Xu, Gustav Akk, Holger A Scheidt, Peter Müller, Douglas F Covey, Alex S Evers, Jacob Kongsted, Daniel Wüstner","doi":"10.1021/acschemneuro.4c00571","DOIUrl":"10.1021/acschemneuro.4c00571","url":null,"abstract":"<p><p>Allopregnanolone (AlloP) is an example of neuroactive steroids (NAS), which is a potent allosteric activator of the γ-aminobutyric acid A (GABA_<i>A</i>) receptor. The mechanisms underlying the biological activity of AlloP and other NAS are only partially understood. Here, we present intrinsically fluorescent analogs of AlloP (MQ-323) and its 3β-epimer, epi-allopregnanolone (E-AlloP) (YX-11), and show, by a combination of spectroscopic and computational studies, that these analogs mimic the membrane properties of AlloP and E-AlloP very well. We found stereospecific differences in the orientation and dynamics of the NAS as well as in their impact on membrane permeability. However, all NAS are unable to condense the lipid bilayer, in stark contrast to cholesterol. Using Förster resonance energy transfer (FRET) and electrophysiological measurements, we show that MQ-323 but not YX-11 binds at the intersubunit site of the ELICα₁GABA_<i>A</i> receptor and potentiates GABA-induced receptor currents. In aqueous solvents, YX-11 forms aggregates at much lower concentrations than MQ-323, and loading both analogs onto cyclodextrin allows for their uptake by human astrocytes, where they become enriched in lipid droplets (LDs), as shown by quantitative fluorescence microscopy. Trafficking of the NAS analogs is stereospecific, as uptake and lipid droplet targeting is more pronounced for YX-11 compared to MQ-323. In summary, we present novel minimally modified analogs of AlloP and E-AlloP, which enable us to reveal stereospecific membrane properties, allosteric receptor activation, and intracellular transport of these neurosteroids. Our fluorescence design strategy will be very useful for the analysis of other NAS in the future.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"4322-4336"},"PeriodicalIF":4.1,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142685393","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":"Unlocking the Potential of Oxymatrine: A Comprehensive Review of Its Neuroprotective Mechanisms and Therapeutic Prospects in Neurological Disorders.","authors":"Yogita Dhurandhar, Shubham Tomar, Ashmita Das, As Pee Singh, Jeevan Lal Prajapati, Surendra H Bodakhe, Kamta P Namdeo","doi":"10.1021/acschemneuro.4c00338","DOIUrl":"10.1021/acschemneuro.4c00338","url":null,"abstract":"<p><p><i>Sophora flavescens</i>, the source of oxymatrine, is gaining popularity due to its potential in neuroprotection and treatment of various neurological conditions like epilepsy, depression, Parkinson's, Alzheimer's and multiple sclerosis. Its natural occurrence and promising preliminary research highlight its ability to reduce nerve cell damage and inflammation, attributed to its antiapoptotic, antioxidant and anti-inflammatory properties. However, challenges like solubility, potential adverse effects and limited bioavailability hinder its full therapeutic utilization. Current strategies, including formulation optimization and innovative drug delivery systems, aim to enhance its efficacy and safety. Despite its potential, further research is necessary to overcome these obstacles and maximize its clinical effectiveness. Conclusively, oxymatrine demonstrates distinct neuroprotective properties, offering unique advantages over other agents currently being studied or used in clinical practice for neurological disorders. nevertheless, additional study is necessary to surmount current obstacles and maximize its effectiveness for clinical settings. This study provides a comprehensive overview of oxymatrine's neuroprotective mechanisms and therapeutic potential while emphasizing the need for continued investigation and development for practical clinical application.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"4245-4257"},"PeriodicalIF":4.1,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612712","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":"Exogenous Amyloid Fibrils Can Cause Significant Upregulation of Neurodegenerative Disease Proteins.","authors":"Xihua Liu, Wenzhe Jia, Yapeng Fang, Yiping Cao","doi":"10.1021/acschemneuro.4c00483","DOIUrl":"10.1021/acschemneuro.4c00483","url":null,"abstract":"<p><p>Neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, are associated with the formation of amyloid fibrils. In familial cases, the mutant causative genes accentuate disease progression through overexpression or misfolding of amyloidogenic proteins. Besides, considerable amyloidosis cases arise from external factors, but their origin and mechanisms are not yet fully understood. Herein, we found that amyloid fibrils generated from egg and milk proteins, in addition to their nutritional effects to intestinal cells, can selectively reduce the viability of nervous cells as well as pancreatic islet cells. In contrast, soy protein amyloid fibrils lacked cytotoxicity to the aforementioned cells. This protein source and cell type-dependent cytotoxicity are demonstrated to be associated with the significant upregulation of amyloidogenic proteins. The finding was also confirmed by the vein injection of beta-lactoglobulin fibrils to mice, exhibiting the pronounced upregulations of amyloid beta_1-42 (Aβ_1-42) and islet amyloid polypeptide in vivo. The study therefore provides insight into the health implications of exogenous amyloid fibrils.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"4284-4294"},"PeriodicalIF":4.1,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453213","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":"Cross-Interactions of Aβ Peptides Implicated in Alzheimer's Disease Shape Amyloid Oligomer Structures and Aggregation.","authors":"Tanja Habeck, Silvana Smilla Zurmühl, António J Figueira, Edvaldo Vasconcelos Soares Maciel, Cláudio M Gomes, Frederik Lermyte","doi":"10.1021/acschemneuro.4c00492","DOIUrl":"10.1021/acschemneuro.4c00492","url":null,"abstract":"<p><p>A defining hallmark of Alzheimer's disease (AD) is the synaptic aggregation of the amyloid β (Aβ) peptide. <i>In vivo</i>, Aβ production results in a diverse mixture of variants, of which Aβ40, Aβ42, and Aβ43 are profusely present in the AD brain, and their relative abundance is recognized to play a role in disease onset and progression. Nonetheless, the occurrence of Aβ40, Aβ42, and Aβ43 hetero-oligomerization and the subsequent effects on Aβ aggregation remain elusive and were investigated here. Using thioflavin-T (ThT)-monitored aggregation assays and native mass spectrometry coupled to ion mobility analysis (IM-MS), we first show that all Aβ peptides are aggregation-competent and self-assemble into homo-oligomers with distinct conformational populations, which are more pronounced between Aβ40 than the longer variants. ThT assays were then conducted on binary mixtures of Aβ variants, revealing that Aβ42 and Aβ43 aggregate independently from Aβ40 but significantly speed up Aβ40 fibrillation. Aβ42 and Aβ43 were observed to aggregate concurrently and mutually accelerate fibril formation, which likely involves hetero-oligomerization. Accordingly, native MS analysis revealed pairwise oligomerization between all variants, with the formation of heterodimers and heterotrimers. Interestingly, IM-MS indicates that hetero-oligomers containing longer Aβ variants are enriched in conformers with lower collision cross-sections when compared to their homo-oligomer counterparts. This suggests that Aβ42 and Aβ43 are capable of remodeling the oligomer structure toward a higher compaction level. Altogether, our findings provide a mechanistic description for the hetero-oligomerization of Aβ variants implicated in AD, contributing to rationalizing their <i>in vivo</i> proteotoxic interplay.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"4295-4304"},"PeriodicalIF":4.1,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674448","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}