ACS Chemical Neuroscience最新文献

Cellular Uptake of Tau Aggregates Triggers Disulfide Bond Formation in Four-Repeat Tau Monomers.

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-12-23 DOI: 10.1021/acschemneuro.4c00607

Brad J Krzesinski, Tyler J Holub, Zachariah Y Gabani, Martin Margittai

{"title":"Cellular Uptake of Tau Aggregates Triggers Disulfide Bond Formation in Four-Repeat Tau Monomers.","authors":"Brad J Krzesinski, Tyler J Holub, Zachariah Y Gabani, Martin Margittai","doi":"10.1021/acschemneuro.4c00607","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00607","url":null,"abstract":"Oxidative stress is an important driver of aging and has been linked to numerous neurodegenerative disorders, including Alzheimer's disease. A key pathological hallmark of Alzheimer's are filamentous inclusions made of the microtubule associated protein Tau. Based on alternative splicing, Tau protein can feature either three or four microtubule binding repeats. Distinctively, three-repeat Tau contains a single cysteine; four-repeat Tau contains two. Although there is evidence that the cysteines in pathological Tau filaments exist in the reduced form, very little is known about the alternative disulfide-bonded state. It is unclear whether it can exist nontransiently in the reducing environment of the cytosol. Such knowledge, however, is important as different redox states of Tau could modulate aggregation. To address this question, we transfected HEK293 cells expressing the P301S variant of four-repeat Tau with fibril seeds composed of compact, disulfide-bonded Tau monomers. In vitro, these fibrils are observed to recruit only compact Tau, but not Tau in which the cysteines are reduced or replaced by alanines or serines. In line with this characteristic, the fibrils dissociate when treated with a reducing agent. When offered to HEK293 cells, variant Tau protein is recruited to the seeds forming intracellular fibrils with the same seeding properties as the in vitro counterparts. Markedly, the proteins in these fibrils have a compact, disulfide-bonded configuration and dissociate upon reduction. These findings reveal that uptake of exogeneous fibril seeds triggers oxidation of Tau monomers, modulating intracellular aggregation.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142875331","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}

引用次数: 0

Brazilin-Rich Extract from Caesalpinia sappan L. Attenuated the Motor Deficits and Neurodegeneration in MPTP/p-Induced Parkinson's Disease Mice by Regulating Gut Microbiota and Inhibiting Inflammatory Responses.

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-12-22 DOI: 10.1021/acschemneuro.4c00679

Wen Gao, Xinni Wu, Yang Wang, Fuping Lu, Fufeng Liu

{"title":"Brazilin-Rich Extract from Caesalpinia sappan L. Attenuated the Motor Deficits and Neurodegeneration in MPTP/p-Induced Parkinson's Disease Mice by Regulating Gut Microbiota and Inhibiting Inflammatory Responses.","authors":"Wen Gao, Xinni Wu, Yang Wang, Fuping Lu, Fufeng Liu","doi":"10.1021/acschemneuro.4c00679","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00679","url":null,"abstract":"Parkinson's disease (PD) is a complicated neurological disease with an unclear pathogenesis. However, dysregulation of gut microbiota and inflammation response play crucial roles in the progression of PD. Caesalpinia sappan L., a traditional medicinal plant containing brazilin as its primary active compound, is known for its anti-inflammatory and neuroprotective properties. However, the impact of C. sappan L. extract (SE) on PD through the regulation of the microbiota-gut-brain axis remains unclear. This study investigated the effects and mechanisms of a 91.23% brazilin-enriched SE on MPTP/p-induced PD mice. Results showed that SE significantly ameliorated motor deficits and protected dopaminergic neurons in PD mice. Additionally, SE reduced oxidative stress and inflammation in the brain. SE also restored gut microbiota by increasing Firmicutes and decreasing Bacteroidetes, alongside enhancing the production of short-chain fatty acids (SCFAs) like butyric acid. Furthermore, SE mitigated intestinal barrier damage by enhancing the expression of ZO-1 and occludin, thereby decreasing lipopolysaccharide leakage and inflammatory factor release. Molecular simulations suggested that butyric acid may maintain intestinal integrity by stabilizing ZO-I and occludin conformations. In conclusion, SE exhibited a protective effect on motor deficits and neurodegeneration in PD by regulating gut microbiota and SCFAs, repairing the intestinal barrier, and mitigating inflammatory responses.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142875329","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}

引用次数: 0

Opposite Roles of Cholesterol and Lanosterol in Lipid Membrane on Amyloid-Beta 42 Peptide Nucleation and Fibril Formation.

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-12-21 DOI: 10.1021/acschemneuro.4c00707

Kyohei Akiho, Akane Iida-Adachi, Hideki Nabika

{"title":"Opposite Roles of Cholesterol and Lanosterol in Lipid Membrane on Amyloid-Beta 42 Peptide Nucleation and Fibril Formation.","authors":"Kyohei Akiho, Akane Iida-Adachi, Hideki Nabika","doi":"10.1021/acschemneuro.4c00707","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00707","url":null,"abstract":"Molecular self-assembly of amyloid-beta peptides to form fibrillar aggregates is a known cause of Alzheimer's disease. Although homogeneous nucleation of amyloid-beta is unfavorable, heterogeneous nucleation of amyloid-beta in cell membranes plays a key role in fibril formation. We observed these opposite roles in the effects of cholesterol and lanosterol, the precursor of cholesterol in the brain, on nucleation. As previously reported, cholesterol accelerated nucleation, whereas lanosterol decelerated it when mixed with dioleoyl-phosphatidylcholine at 20%. The observed opposite effects of cholesterol and lanosterol on nucleation do not correlate with the differences in the mechanical and thermodynamic nature of mixed membranes. However, the affinity of amyloid-beta to the inner membrane seems to be related to the opposite effects on nucleation kinetics. Cholesterol reduced the insertion of amyloid-beta into the lipid membrane, whereas lanosterol promoted the insertion of amyloid-beta into the membrane, which would make amyloid-beta more tightly bound by lipid molecules and reduce its diffusivity in the membrane and consequently inhibit nucleation. Our study provides insights into the effects of sterol compounds other than the well-investigated cholesterol on the self-assembly of amyloid-beta to clarify the molecular basis underlying Alzheimer's disease pathology and to develop targeted therapeutic strategies.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142870572","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}

引用次数: 0

3D Super-Resolution Imaging of PSD95 Reveals an Abundance of Diffuse Protein Supercomplexes in the Mouse Brain.

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-12-19 DOI: 10.1021/acschemneuro.4c00684

Sam Daly, Edita Bulovaite, Anoushka Handa, Katie Morris, Leila Muresan, Candace Adams, Takeshi Kaizuka, Alexandre Kitching, Alexander Spark, Gregory Chant, Kevin O Holleran, Seth G N Grant, Mathew H Horrocks, Steven F Lee

{"title":"3D Super-Resolution Imaging of PSD95 Reveals an Abundance of Diffuse Protein Supercomplexes in the Mouse Brain.","authors":"Sam Daly, Edita Bulovaite, Anoushka Handa, Katie Morris, Leila Muresan, Candace Adams, Takeshi Kaizuka, Alexandre Kitching, Alexander Spark, Gregory Chant, Kevin O Holleran, Seth G N Grant, Mathew H Horrocks, Steven F Lee","doi":"10.1021/acschemneuro.4c00684","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00684","url":null,"abstract":"PSD95 is an abundant scaffolding protein that assembles multiprotein complexes controlling synaptic physiology and behavior. Confocal microscopy has previously shown that PSD95 is enriched in the postsynaptic terminals of excitatory synapses and two-dimensional (2D) super-resolution microscopy further revealed that it forms nanoclusters. In this study, we utilized three-dimensional (3D) super-resolution microscopy to examine the nanoarchitecture of PSD95 in the mouse brain, characterizing the spatial arrangement of over 8 million molecules. While we were able to identify molecular arrangements that have been previously reported, imaging in 3D allowed us to classify these with higher accuracy. Furthermore, 3D super-resolution microscopy enabled the quantification of protein levels, revealing that an abundance of PSD95 molecules existed outside of synapses as a diffuse population of supercomplexes, containing multiple copies of PSD95. Further analysis of the supercomplexes containing two units identified two populations: one that had PSD95 molecules separated by 39 ± 2 nm, and a second with a separation of 94 ± 27 nm. The finding that there exists supercomplexes containing two PSD95 units outside of the synapse suggests that supercomplexes containing multiple protein copies assemble outside the synapse and then integrate into the synapse to form a supramolecular nanocluster architecture.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862501","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}

引用次数: 0

Lipopolysaccharide Effects on Neurotransmission: Understanding Implications for Depression. 脂多糖对神经传递的影响：了解对抑郁症的影响

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-12-18 Epub Date: 2024-11-27 DOI: 10.1021/acschemneuro.4c00591

L Batey, B Baumberger, H Khoshbouei, P Hashemi

引用次数: 0

Imidazo[2,1-b][1,3]thiazine Derivatives as Potential Modulators of Alpha-Synuclein Amyloid Aggregation. 咪唑并[2,1-b][1,3]噻嗪衍生物作为阿尔法-突触核蛋白淀粉样蛋白聚合的潜在调节剂

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-12-18 Epub Date: 2024-11-27 DOI: 10.1021/acschemneuro.4c00451

Indrė Misiu Naitė, Kamilė Mikalauskaitė, Martyna Paulauskaitė, Ru Ta Sniečkutė, Vytautas Smirnovas, Algirdas Brukštus, Mantas Žiaunys, Ieva Žutautė

{"title":"Imidazo[2,1-b][1,3]thiazine Derivatives as Potential Modulators of Alpha-Synuclein Amyloid Aggregation.","authors":"Indrė Misiu Naitė, Kamilė Mikalauskaitė, Martyna Paulauskaitė, Ru Ta Sniečkutė, Vytautas Smirnovas, Algirdas Brukštus, Mantas Žiaunys, Ieva Žutautė","doi":"10.1021/acschemneuro.4c00451","DOIUrl":"10.1021/acschemneuro.4c00451","url":null,"abstract":"Insoluble amyloid fibrils accumulate in the intercellular spaces of organs and tissues, leading to various amyloidosis-related disorders in the human body. Specifically, Parkinson's disease is associated with the aggregation of alpha-synuclein. However, current treatments for Parkinson's primarily focus on managing motor symptoms and slowing disease progression. Efforts to prevent and halt the progression of these diseases involve the search for small molecular compounds. In this work, we synthesized imidazo[2,1-b][1,3]thiazines in an atom-economic way by cyclization of 2-alkynylthioimidazoles using 10% AuCl as the catalyst. We identified several compounds with specific functional groups capable of both inhibiting the aggregation of alpha-synuclein and redirecting the fibril formation pathway. The investigation into how these substances function revealed that imidazo[2,1-b][1,3]thiazine derivatives can influence alpha-synuclein aggregation in several ways. They not only inhibit the primary nucleation process and maintain a balance toward nonaggregated protein states but also stabilize smaller oligomeric species of alpha-synuclein and cause the formation of fibrils with unique structures and forms. These imidazo[2,1-b][1,3]thiazines could potentially be used in developing highly efficient, small molecular weight protein aggregation inhibitors.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"4418-4430"},"PeriodicalIF":4.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142737731","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}

引用次数: 0

Patent Review of Novel Biologics Targeting Opioid Use Disorder (2018-2024). 针对阿片类药物使用障碍的新型生物制剂专利回顾（2018-2024 年）》。

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-12-18 Epub Date: 2024-11-28 DOI: 10.1021/acschemneuro.4c00691

Samuel Obeng, Lance R McMahon, Edward Ofori

{"title":"Patent Review of Novel Biologics Targeting Opioid Use Disorder (2018-2024).","authors":"Samuel Obeng, Lance R McMahon, Edward Ofori","doi":"10.1021/acschemneuro.4c00691","DOIUrl":"10.1021/acschemneuro.4c00691","url":null,"abstract":"Drug overdose deaths in 2023 in the United States exceeded 107,000, with 80,000 of these deaths attributed to opioids alone. The emergence of synthetic opioids such as fentanyl and its analogues have worsened the opioid overdose epidemic. A novel approach to treat opioid overdose and opioid use disorder (OUD) has been the introduction of biologics, which include monoclonal antibodies that bind to circulating opioids, preventing them from reaching the central nervous system, or peptides that have antinociceptive effects but lack the abuse liability of synthetic opioids. A challenge in the treatment of opioid overdose has been renarcotization, where an overdose patient revived with naloxone can re-enter an overdose state from residual opioid in the body. Biologics such as vaccines and monoclonal antibodies are excellent strategies that have been demonstrated to prevent renarcotization. In this review, we retrieved and discussed patents filed in the past six (6) years that focus on novel biologics reported as treatments for opioid overdose and OUD. We also provide a perspective on the use of biologics as therapeutics for OUD and opioid overdose.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"4360-4368"},"PeriodicalIF":4.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142737736","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}

引用次数: 0

Effect of a SARS-CoV-2 Protein Fragment on the Amyloidogenic Propensity of Human Islet Amyloid Polypeptide. SARS-CoV-2 蛋白片段对人胰岛淀粉样多肽致淀粉样倾向的影响

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-12-18 Epub Date: 2024-11-24 DOI: 10.1021/acschemneuro.4c00473

Marvin Bilog, Jennifer Cersosimo, Iliana Vigil, Ruel Z B Desamero, Adam A Profit

{"title":"Effect of a SARS-CoV-2 Protein Fragment on the Amyloidogenic Propensity of Human Islet Amyloid Polypeptide.","authors":"Marvin Bilog, Jennifer Cersosimo, Iliana Vigil, Ruel Z B Desamero, Adam A Profit","doi":"10.1021/acschemneuro.4c00473","DOIUrl":"10.1021/acschemneuro.4c00473","url":null,"abstract":"Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the onset of COVID-19 have been linked to an increased risk of developing type 2 diabetes. While a variety of mechanisms may ultimately be responsible for the onset of type 2 diabetes under these circumstances, one mechanism that has been postulated involves the increased aggregation of human islet amyloid polypeptide (hIAPP) through direct interaction with SARS-CoV-2 viral proteins. Previous computational studies investigating this possibility revealed that a nine-residue peptide fragment known as SK9 (SFYVYSRVK) from the SARS-CoV-2 envelope protein can stabilize the native conformation of hIAPP1-37 by interacting with the N-terminal region of amylin. One of the areas particularly stabilized through this interaction encompasses residues 15-28 of amylin. Given these findings, we investigated whether SK9 could interact with short amyloidogenic sequences derived from this region of amylin. Here, we employ docking studies, molecular dynamics simulations, and biophysical techniques to provide theoretical as well as direct experimental evidence that SK9 can interact with hIAPP12-18 and hIAPP20-29 peptides. Furthermore, we demonstrate that SK9 not only can interact with these sequences but also serves to prevent the self-assembly of these amyloidogenic peptides. In striking contrast, we also show that SK9 has little effect on the amyloidogenic propensity of full-length amylin. These findings are contrary to previous published simulations involving SK9 and hIAPP1-37. Such observations may assist in clarifying potential mechanisms of the SARS-CoV-2 interaction with hIAPP and its relevance to the onset of type 2 diabetes in the setting of COVID-19.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"4431-4440"},"PeriodicalIF":4.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142708490","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}

引用次数: 0

A VEGF Fragment Encompassing Residues 10-30 Inhibits Aβ1-42 Amyloid Aggregation and Exhibits Neuroprotective Properties Matching the Full-Length Protein. 包含 10-30 位残基的血管内皮生长因子片段可抑制 Aβ1-42 淀粉样蛋白聚集，并表现出与全长蛋白相匹配的神经保护特性。

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-12-18 Epub Date: 2024-11-25 DOI: 10.1021/acschemneuro.4c00669

Stefania Zimbone, M Laura Giuffrida, Michele F M Sciacca, Rita Carrotta, Fabio Librizzi, Danilo Milardi, Giulia Grasso

{"title":"A VEGF Fragment Encompassing Residues 10-30 Inhibits Aβ1-42 Amyloid Aggregation and Exhibits Neuroprotective Properties Matching the Full-Length Protein.","authors":"Stefania Zimbone, M Laura Giuffrida, Michele F M Sciacca, Rita Carrotta, Fabio Librizzi, Danilo Milardi, Giulia Grasso","doi":"10.1021/acschemneuro.4c00669","DOIUrl":"10.1021/acschemneuro.4c00669","url":null,"abstract":"The intricate relationship between brain vascular diseases and neurodegeneration has garnered increased attention in the scientific community. With an aging population, the incidence of these two conditions is likely to increase, making it imperative to understand the underlying common molecular mechanisms and unveiling novel avenues for therapy. Prompted by the observation that Aβ peptide aggregation has been implicated in the development of cerebral amyloid angiopathy (CAA) and that elevated concentrations of vascular endothelial growth factor (VEGF) in the cerebrospinal fluid (CSF) have been correlated with less cognitive decline in Alzheimer's disease (AD), we demonstrate that a small peptide (Pep9) encompassing the 10-30 sequence of VEGF exhibits significant ability to inhibit the aggregation of the Aβ1-42 peptide, as well as the formation of toxic oligomers. AFM studies confirmed this inhibitory capacity, which is also paralleled by a significant reduction of the random coil to a beta-sheet conformational transition. Further studies have shown that Pep9 protects differentiated neuroblastoma SH-SY5Y cells from Aβ toxicity, being even more effective than full-length protein in preventing amyloid-induced neuronal death. The use of a control peptide wherein two histidines are substituted with glycines (H11G and H12G) suggests a close relationship between the peptide amino acid sequence and its antiaggregating/neuroprotective activity. Overall, this study provides insight into the role of VEGF in AD and suggests that specific VEGF fragments could be beneficial in the treatment of this condition.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"4580-4590"},"PeriodicalIF":4.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142714757","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}

引用次数: 0

Neuroreceptor Mapping in 2024.

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-12-18 Epub Date: 2024-12-09 DOI: 10.1021/acschemneuro.4c00754

Ramya Tokala, Jacob M Hooker

引用次数: 0