ACS Chemical Neuroscience最新文献

{"title":"Identification and In Vitro and In Vivo Characterization of KAC-50.1 as a Potential α-Synuclein PET Radioligand","authors":"Dinahlee Saturnino Guarino*,&nbsp;Patricia Miranda Azpiazu,&nbsp;Dan Sunnemark,&nbsp;Charles S. Elmore,&nbsp;Jonas Bergare,&nbsp;Markus Artelsmair,&nbsp;Gunnar Nordvall,&nbsp;Anton Forsberg Morén,&nbsp;Zhisheng Jia,&nbsp;Miguel Cortes-Gonzalez,&nbsp;Robert H. Mach,&nbsp;Kyle C. Wilcox,&nbsp;Sjoerd Finnema,&nbsp;Magnus Schou and Andrea Varrone*,&nbsp;","doi":"10.1021/acschemneuro.4c0049310.1021/acschemneuro.4c00493","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00493https://doi.org/10.1021/acschemneuro.4c00493","url":null,"abstract":"<p >The accumulation of aggregated α-synuclein (α-syn) is a pathological hallmark of Parkinson’s disease (PD) and other synucleinopathies. Here within, we report the in vitro characterization targeting site 2 of α-syn fibrils and in vivo evaluation of NHPs of KAC-50.1 as a potential α-syn positron emission tomography (PET) radioligand. Preclinical studies were performed using a multidimensional approach of post-mortem brain imaging techniques, radioligand binding, and biochemical studies. These experiments were followed by PET imaging in cynomolgus monkeys using [¹¹C]KAC-50.1. [3H]KAC-50.1 displayed a KD of 35 nM toward site 2 in recombinant α-syn fibrils. Specific binding of [3H]KAC-50.1 was observed in brain tissues with abundant α-syn pathology but also in AD, PSP, and CBD cases, indicating binding to amyloid β (Aβ) and tau pathology. PET studies showed a rapid entrance of [¹¹C]KAC-50.1 into the brain and relatively rapid washout from cortical brain regions, with slower washout in subcortical regions. [3H]KAC-50.1 is a ligand that binds to fibrillar α-syn but shows limited selectivity for α-syn versus Aβ and tau fibrils. PET studies in NHPs indicate that [¹¹C]KAC-50.1, despite reversible kinetic properties, displays retention in white matter. Altogether, the in vitro and in vivo properties do not support further development of [¹¹C]KAC-50.1 as a PET imaging agent.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"15 22","pages":"4210–4219 4210–4219"},"PeriodicalIF":4.1,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acschemneuro.4c00493","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142671636","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":"Aromatic Amino Acid Hydroxylases as Off-Targets of Histone Deacetylase Inhibitors","authors":"Anne Baumann,&nbsp;Niklas Papenkordt,&nbsp;Dina Robaa,&nbsp;Peter D. Szigetvari,&nbsp;Anja Vogelmann,&nbsp;Franz Bracher,&nbsp;Wolfgang Sippl,&nbsp;Manfred Jung and Jan Haavik*,&nbsp;","doi":"10.1021/acschemneuro.4c0034610.1021/acschemneuro.4c00346","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00346https://doi.org/10.1021/acschemneuro.4c00346","url":null,"abstract":"<p >The aromatic amino acid hydroxylases (AAAHs) phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylases 1 and 2 are structurally related enzymes that contain an active site iron atom and depend on tetrahydrobiopterin (BH₄) as cosubstrate. Due to their important roles in synthesis of serotonin, dopamine, noradrenaline, and adrenaline and their involvement in cardiovascular, neurological, and endocrine disorders, AAAHs have been targeted by substrate analogs, iron chelators, and allosteric ligands. Phenylalanine hydroxylase is also off-target of the histone deacetylase (HDAC) inhibitor panobinostat. To systematically explore the binding of HDAC inhibitors to AAAHs, we screened a library of 307 HDAC inhibitors and structural analogs against tryptophan hydroxylase 1 using a fluorescence-based thermal stability assay, followed by activity assays. Selected hits were enzymatically tested against all four purified human AAAHs. Cellular thermal shift assay was performed for phenylalanine hydroxylase. We show that panobinostat and structurally related compounds such as TB57, which similarly to panobinostat also contains a cinnamoyl hydroxamate, bind to human AAAHs and inhibit these enzymes with high selectivity within the class (panobinostat inhibition (IC₅₀): phenylalanine hydroxylase (18 nM) &gt; tyrosine hydroxylase (450 nM) &gt; tryptophan hydroxylase 1 (1960 nM). This study shows that panobinostat and related hydroxamic acid type HDAC inhibitors inhibit all AAAHs at therapeutically relevant concentrations. Our results warrant further investigations of the off-target relevance of HDAC inhibitors intended for clinical use and provide directions for new dual HDAC/AAAH and selective AAAH inhibitors. These findings may also provide a new mechanistic link between regulation of histone modification, AAAH function, and monoaminergic neurotransmission.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"15 22","pages":"4143–4155 4143–4155"},"PeriodicalIF":4.1,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acschemneuro.4c00346","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142671643","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":"Dexmedetomidine Attenuates Neuroinflammation-Mediated Hippocampal Neurogenesis Impairment in Sepsis-Associated Encephalopathy Mice through Central α2A-Adrenoceptor","authors":"Xinlong Zhang,&nbsp;Yue Feng,&nbsp;Yi Zhong,&nbsp;Rui Ding,&nbsp;Yaoyi Guo,&nbsp;Fan Jiang,&nbsp;Yan Xing,&nbsp;Hongwei Shi,&nbsp;Hongguang Bao and Yanna Si*,&nbsp;","doi":"10.1021/acschemneuro.4c0048610.1021/acschemneuro.4c00486","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00486https://doi.org/10.1021/acschemneuro.4c00486","url":null,"abstract":"<p >Sepsis-associated encephalopathy (SAE), one of the common complications of sepsis, is associated with higher ICU mortality, prolonged hospitalization, and long-term cognitive decline. Sepsis can induce neuroinflammation, which negatively affects hippocampal neurogenesis. Dexmedetomidine has been shown to protect against SAE. However, the potential mechanism remains unclear. In this study, we added lipopolysaccharide (LPS)-stimulated astrocytes-conditioned media (LPS-CM) to neural stem cells (NSCs) culture, which were pretreated with dexmedetomidine in the presence or absence of the α2-adrenoceptor antagonist yohimbine or the α2A-adrenoceptor antagonist BRL-44408. LPS-CM impaired the neurogenesis of NSCs, characterized by decreased proliferation, enhanced gliogenesis, and declined viability. Dexmedetomidine alleviated LPS-CM-induced impairment of neurogenesis in a dose-dependent manner. Yohimbine, as well as BRL-44408, reversed the effects of dexmedetomidine. We established a mouse model of SAE via cecal ligation and perforation (CLP). CLP-induced astrocyte-related neuroinflammation and hippocampal neurogenesis deficits, accompanied by learning and memory decline, which were reversed by dexmedetomidine. The effect of dexmedetomidine was blocked by BRL-44408. Collectively, our findings support the conclusion that dexmedetomidine can protect against SAE, likely mediated by the combination of inhibiting neuroinflammation via the astrocytic α2A-adrenoceptor with attenuating neuroinflammation-induced hippocampal neurogenesis deficits via NSCs α2A-adrenoceptor.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"15 22","pages":"4185–4201 4185–4201"},"PeriodicalIF":4.1,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142671901","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":"SARS-CoV-2 and HSV-1 Induce Amyloid Aggregation in Human CSF Resulting in Drastic Soluble Protein Depletion","authors":"Wanda Christ,&nbsp;Sebastian Kapell,&nbsp;Michal J. Sobkowiak,&nbsp;Georgios Mermelekas,&nbsp;Björn Evertsson,&nbsp;Helena Sork,&nbsp;Osama Saher,&nbsp;Safa Bazaz,&nbsp;Oskar Gustafsson,&nbsp;Eduardo I. Cardenas,&nbsp;Viviana Villa,&nbsp;Roberta Ricciarelli,&nbsp;Johan K. Sandberg,&nbsp;Jonas Bergquist,&nbsp;Andrea Sturchio,&nbsp;Per Svenningsson,&nbsp;Tarja Malm,&nbsp;Alberto J. Espay,&nbsp;Maria Pernemalm,&nbsp;Anders Lindén,&nbsp;Jonas Klingström,&nbsp;Samir El Andaloussi and Kariem Ezzat*,&nbsp;","doi":"10.1021/acschemneuro.4c0063610.1021/acschemneuro.4c00636","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00636https://doi.org/10.1021/acschemneuro.4c00636","url":null,"abstract":"<p >The corona virus (SARS-CoV-2) pandemic and the resulting long-term neurological complications in patients, known as long COVID, have renewed interest in the correlation between viral infections and neurodegenerative brain disorders. While many viruses can reach the central nervous system (CNS) causing acute or chronic infections (such as herpes simplex virus 1, HSV-1), the lack of a clear mechanistic link between viruses and protein aggregation into amyloids, a characteristic of several neurodegenerative diseases, has rendered such a connection elusive. Recently, we showed that viruses can induce aggregation of purified amyloidogenic proteins via the direct physicochemical mechanism of heterogeneous nucleation (HEN). In the current study, we show that the incubation of HSV-1 and SARS-CoV-2 with human cerebrospinal fluid (CSF) leads to the amyloid aggregation of several proteins known to be involved in neurodegenerative diseases, such as APLP1 (amyloid β precursor like protein 1), ApoE, clusterin, α2-macroglobulin, PGK-1 (phosphoglycerate kinase 1), ceruloplasmin, nucleolin, 14-3-3, transthyretin, and vitronectin. Importantly, UV-inactivation of SARS-CoV-2 does not affect its ability to induce amyloid aggregation, as amyloid formation is dependent on viral surface catalysis via HEN and not its ability to replicate. Additionally, viral amyloid induction led to a dramatic drop in the soluble protein concentration in the CSF. Our results show that viruses can physically induce amyloid aggregation of proteins in human CSF and result in soluble protein depletion, thus providing a potential mechanism that may account for the association between persistent and latent/reactivating brain infections and neurodegenerative diseases.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"15 22","pages":"4095–4104 4095–4104"},"PeriodicalIF":4.1,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142671380","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":"L-DOPA Promotes Functional Proliferation Through GPR143, Specific L-DOPA Receptor of Astrocytes","authors":"Ye-Ji Kim,&nbsp;Gyeong Min Park,&nbsp;Woo Kyung Cho* and Dong Ho Woo*,&nbsp;","doi":"10.1021/acschemneuro.4c0031110.1021/acschemneuro.4c00311","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00311https://doi.org/10.1021/acschemneuro.4c00311","url":null,"abstract":"<p >l-3,4-Dihydroxyphenylalanine (levodopa and L-DOPA in this text), alongside dopamine, boasts high biocompatibility, prompting industrial demand for its use as a coating material. Indeed, the effectiveness of L-DOPA is steadily rising as it serves as an oral therapeutic agent for neurodegenerative brain diseases, particularly Parkinson’s disease (PD). However, the effects of L-DOPA on the growth and function of astrocytes, the main glial cells, and the most numerous glial cells in the brain, are unknown. Here, we investigated whether L-DOPA is possible as a coating material on cover glass and polystyrene for rat primary astrocytes. The coating state of L-DOPA on the cover glass and polystyrene was characterized by X-ray photoelectron spectroscopy (XPS) and static water contact angle (WCA). Interestingly, L-DOPA coated on the cover glass promoted the proliferation of astrocytes but not neurons. Furthermore, L-DOPA coated on the cover glass, as opposed to polystyrene, facilitated the proliferation of the astrocytes. The astrocytes grown on L-DOPA-coated cover glasses exhibited functional receptor-activated Ca²⁺ transients through the activation of protease-activated receptor subtype 1 (PAR-1), recognized as an astrocytic functional marker. However, cover glass coated with 0, 500, 1000, 2000, and 4000 μg/mL L-DOPA maintained astrocyte viability, while supplementation with 500 and 1000 μM L-DOPA significantly decreased astrocyte viability. This suggests that treatments with free 500 and 1000 μM L-DOPA significantly reduced the number of astrocytes. Both Pimozide, an inhibitor of G protein-coupled receptor 143 (GPR143), also known as Ocular albinism type 1 (OA1), and CCG2046, an inhibitor of regulator of G protein signaling 4 (RGS4), reduced the viability of astrocytes on cover glass coated with L-DOPA compared to astrocytes on cover glass coated with poly-<span>d</span>-lysine (PDL). This suggests that L-DOPA promotes astrocyte proliferation through activation of the GPR143 signaling pathway. These findings imply that L-DOPA proliferates functional astrocytes through the activation of GPR143. These results are the first report that L-DOPA coating cover glass proliferates rat primary astrocytes with the activation of GPR143. The discovery that levodopa enhances cell adhesion can significantly influence research in multiple ways. It provides insights into cell behavior, disease mechanisms, and potential therapeutic applications in tissue engineering and regenerative medicine. Additionally, it offers opportunities to explore novel approaches for improving cell-based therapies and tissue regeneration. Overall, this finding opens up new avenues for research, with broad implications across various scientific fields.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"15 22","pages":"4132–4142 4132–4142"},"PeriodicalIF":4.1,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142671391","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":"Unveiling the Human Brain on a Chip: An Odyssey to Reconstitute Neuronal Ensembles and Explore Plausible Applications in Neuroscience.","authors":"Subhadra Nandi, Satyajit Ghosh, Shubham Garg, Surajit Ghosh","doi":"10.1021/acschemneuro.4c00388","DOIUrl":"10.1021/acschemneuro.4c00388","url":null,"abstract":"<p><p>The brain is an incredibly complex structure that consists of millions of neural networks. In developmental and cellular neuroscience, probing the highly complex dynamics of the brain remains a challenge. Furthermore, deciphering how several cues can influence neuronal growth and its interactions with different brain cell types (such as astrocytes and microglia) is also a formidable task. Traditional <i>in vitro</i> macroscopic cell culture techniques offer simple and straightforward methods. However, they often fall short of providing insights into the complex phenomena of neuronal network formation and the relevant microenvironments. To circumvent the drawbacks of conventional cell culture methods, recent advancements in the development of microfluidic device-based microplatforms have emerged as promising alternatives. Microfluidic devices enable precise spatiotemporal control over compartmentalized cell cultures. This feature facilitates researchers in reconstituting the intricacies of the neuronal cytoarchitecture within a regulated environment. Therefore, in this review, we focus primarily on modeling neuronal development in a microfluidic device and the various strategies that researchers have adopted to mimic neurogenesis on a chip. Additionally, we have presented an overview of the application of brain-on-chip models for the recapitulation of the blood-brain barrier and neurodegenerative diseases, followed by subsequent high-throughput drug screening. These lab-on-a-chip technologies have tremendous potential to mimic the brain on a chip, providing valuable insights into fundamental brain processes. The brain-on-chip models will also serve as innovative platforms for developing novel neurotherapeutics to address several neurological disorders.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"3828-3847"},"PeriodicalIF":4.1,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491028","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":"Classics in Chemical Neuroscience: Medetomidine.","authors":"Pedro de Andrade Horn, Tomayo I Berida, Lauren C Parr, Jacob L Bouchard, Navoda Jayakodiarachchi, Daniel C Schultz, Craig W Lindsley, Morgan L Crowley","doi":"10.1021/acschemneuro.4c00583","DOIUrl":"10.1021/acschemneuro.4c00583","url":null,"abstract":"<p><p>Medetomidine is an FDA-approved α₂-adrenoreceptor (α₂-AR) agonist used as a veterinary sedative due to its analgesic, sedative, and anxiolytic properties. While it is marketed for veterinary use as a racemic mixture under the brand name Domitor, the pharmacologically active enantiomer, dexmedetomidine, is approved for sedation and analgesia in the hospital setting. Medetomidine has recently been detected in the illicit drug supply alongside fentanyl, xylazine, cocaine, and heroin, producing pronounced sedative effects that are not reversed by naloxone. The pharmacological effects along with the low cost of supply and lack of regulation for medetomidine has made it a target for misuse. Since 2022, medetomidine has been found as an adulterant in samples of seized drugs, as well as in toxicological analyses of patients admitted to the emergency department after suspected overdoses across several U.S. states and Canada. This Review will discuss the history, chemistry, structure-activity relationships, drug metabolism and pharmacokinetics (DMPK), pharmacology, and emergence of medetomidine as an adulterant in drug mixtures in the context of the current opioid drug crisis.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"3874-3883"},"PeriodicalIF":4.1,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11587509/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453209","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":"Bile Acids as Modulators of α-Synuclein Aggregation: Implications for Parkinson's Therapy.","authors":"Harpreet Kaur, Devansh Swadia, Sharmistha Sinha","doi":"10.1021/acschemneuro.4c00459","DOIUrl":"10.1021/acschemneuro.4c00459","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a neurodegenerative disorder characterized by the aggregation of α-synuclein into toxic amyloid fibrils. Recent research suggests that bile acids altered in PD may influence their aggregation. This study investigates the effects of lithocholic acid (LCA) and deoxycholic acid (DCA) on α-synuclein aggregation and toxicity. LCA significantly accelerates aggregation, reducing the lag phase by 75%, while DCA has a milder impact, decreasing the lag phase by 30%. Binding studies show that LCA interacts with the NAC region and DCA with the N-terminal region of α-synuclein. Aggregation assays and electrophoresis reveal that LCA promotes the formation of toxic, SDS-resistant oligomers more effectively than DCA. Cytotoxicity assays confirm a lower cell viability in LCA-treated samples. Additionally, combined LCA and DCA treatment results in enhanced aggregation and toxicity, indicating a synergistic effect. These findings highlight the role of bile acids in α-synuclein aggregation and PD pathogenesis, suggesting that targeting bile acid metabolism could be a therapeutic strategy for PD.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"4055-4065"},"PeriodicalIF":4.1,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453207","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":"Disruption of PHF6 Peptide Aggregation from Tau Protein: Mechanisms of Palmatine Chloride in Preventing Early PHF6 Aggregation.","authors":"Charline Fagnen, Johanna Giovannini, Thomas Vignol, Marc Since, Marco Catto, Anne Sophie Voisin-Chiret, Jana Sopkova-de Oliveira Santos","doi":"10.1021/acschemneuro.4c00353","DOIUrl":"10.1021/acschemneuro.4c00353","url":null,"abstract":"<p><p>The formation of neurofibrillary tangles (NFTs), composed of tau protein aggregates, is a hallmark of neurodegenerative diseases known as tauopathies, including Alzheimer's disease (AD). NFTs consist of paired helical filaments (PHFs) of tau protein with a dominant β-sheet secondary structure. Within these PHFs, the PHF6 hexapeptide (Val₃₀₆-Gln-Ile-Val-Tyr-Lys₃₁₁) has been commonly highlighted as a key site for tau protein nucleation. Palmatine chloride (PC) has been identified as an inhibitor of PHF6 aggregation, capable of reducing aggregation propensity at submicromolar concentrations. In pursuit of novel anti-AD drugs targeting early tau aggregation stages, we conducted an <i>in silico</i> study to elucidate PC's mechanism of action during PHF6 aggregation. Our observations suggest that while PHF6 can still initiate self-aggregation in the presence of PC, PC molecules subtly influence PHF6 aggregation dynamics, favoring smaller aggregates over larger complexes. The study underlined the key roles of aromatic rings in PC binding to different PHF6 aggregates by interacting through π-π stacking with the PHF6 Tyr310 side chain. The presence of aromatic rings in compounds to be able to inhibit the earlier complexation phase seems to be essential. These <i>in silico</i> findings lay a foundation for the design of compounds that could intervene in resolving the neurotoxicity of protein aggregates in AD.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"3981-3990"},"PeriodicalIF":4.1,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453210","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":"Comment on \"Extracellular Vesicles Slow Down Aβ(1-42) Aggregation by Interfering with the Amyloid Fibril Elongation Step\".","authors":"Mohsin Shafiq, Andreu Matamoros-Angles, Sussane Caroline Meister, Markus Glatzel","doi":"10.1021/acschemneuro.4c00601","DOIUrl":"10.1021/acschemneuro.4c00601","url":null,"abstract":"<p><p>Halipi et al. explored the impact of extracellular vesicles (EVs) on amyloid-β (Aβ) aggregation. They concluded that EVs reduce Aβ aggregation, as seen by shorter and thicker fibrils. While we agree with the complex role of EVs in Alzheimer's disease, we are sceptical of the claim that EVs slow down Aβ aggregation, noting missing key references. Previous literature rather suggests that EVs (derived from neuronal cell lines) accelerate the process of Aβ fibrillation and plaque formation. Halipi et al.'s findings may be skewed due to the lack of essential neuronally expressed Aβ-binding partners, like the prion protein (PrP^C) in their EV samples. The commentary, in the light of included original experiments and cited literature, suggests that membrane proteins like PrP^C are crucial to fully understand the role of EVs in Aβ aggregation, and Halipi et al.'s conclusions should be reexamined in light of these factors.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"3791-3793"},"PeriodicalIF":4.1,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11587504/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142386350","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}