ACS Chemical Neuroscience最新文献_第9页

The Interplay between MiR-134/BDNF and LKB1/AMPK/SIRT1 Accentuates the Antidepressant Efficacy of Empagliflozin in Ovariectomized Rats. MiR-134/BDNF和LKB1/AMPK/SIRT1之间的相互作用增强了Empagliflozin对卵巢切除大鼠的抗抑郁疗效

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-09-30 DOI: 10.1021/acschemneuro.4c00313

Nevine Fathy, Merna A Labib, Reham M Essam, Noha A El-Boghdady

{"title":"The Interplay between MiR-134/BDNF and LKB1/AMPK/SIRT1 Accentuates the Antidepressant Efficacy of Empagliflozin in Ovariectomized Rats.","authors":"Nevine Fathy, Merna A Labib, Reham M Essam, Noha A El-Boghdady","doi":"10.1021/acschemneuro.4c00313","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00313","url":null,"abstract":"Major depressive disorder (MDD) is considered a major cause of suicide worldwide. As previous studies revealed that neuroinflammation is a significant factor in the etiology of MDD, this study proposed to unravel the possible antidepressant effect of Empagliflozin (EMPA) through targeting miRNA-134 (miR-134)/brain-derived neurotrophic factor (BDNF) and liver kinase B1 (LKB1)/adenosine 5'-monophosphate-activated protein kinase (AMPK)/silent information regulator 1 (SIRT1) axes in ovariectomized (OVX) female rats. Rats were assigned randomly to four groups: Sham operation (SO), OVX, OVX + EMPA (10 mg/kg/day, p.o.), and OVX + EMPA + Dorsomorphin (DORSO) (25 μg/day/rat, i.v.). Drugs were administered for 28 days after 2 weeks of surgery. EMPA debilitated OVX-induced depressive-like behavior by mitigating the immobility time in the tail suspension test and forced swimming test. Moreover, EMPA curtailed OVX-induced alterations of serum estradiol, hippocampal serotonin, miR-134 expression, as well as BDNF. EMPA also dwindled OVX-induced changes of hippocampal p-LKB1/LKB1, p-AMPK/AMPK, SIRT1, and inflammatory markers (nuclear factor-kappa-B, interleukin-1 beta, interleukin-6, and tumor necrosis factor alpha). Additionally, the EMPA-treated group exhibited marked improvement in different brain regions' histopathology. However, DORSO coadministration reversed most of EMPA's beneficial effects. The current study displayed the modulatory role of EMPA on miR-134/BDNF and LKB1/AMPK/SIRT1 axes, thus offering a partial explanation of its antidepressant efficacy and proposing EMPA as a novel therapeutic avenue for MDD.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337195","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

Comparison of Neurogenesis Promotion Effects between Cinnamoylquinic Acids in Neural Stem Cells from Adult Mice Brains. 比较肉桂酰奎宁酸对成年小鼠脑神经干细胞神经发生的促进作用

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-09-30 DOI: 10.1021/acschemneuro.4c00329

Hongyu Lin, Kazunori Sasaki, Farhana Ferdousi, Hiroko Isoda

{"title":"Comparison of Neurogenesis Promotion Effects between Cinnamoylquinic Acids in Neural Stem Cells from Adult Mice Brains.","authors":"Hongyu Lin, Kazunori Sasaki, Farhana Ferdousi, Hiroko Isoda","doi":"10.1021/acschemneuro.4c00329","DOIUrl":"10.1021/acschemneuro.4c00329","url":null,"abstract":"Caffeoylquinic acids (CQAs) and feruloylquinic acids (FQAs), as cinnamoylquinic acids, have neurogenesis promotion effects. We studied for the first time the neurogenesis-enhancing effect of 3,4,5-tri-feruloylquinic acid (TFQA) compared to 3,4,5-tri-caffeoylquinic acid (TCQA), which has a similar structure, and explored their different cellular and molecular mechanisms in neural stem cells (NSCs) of mice brains. After 2 weeks of incubation, we first assessed the number and size of NSCs in TCQA and TFQA treatments. In NSCs treated for TCQA and TFQA, the NSC proliferation gene expression as well as neuronal and glial cell differentiation gene expressions improved. In the microarray assay, the erythroblastic oncogene B (ErbB) signaling pathway, as the common signaling of TCQA and TFQA treatments, was focused on and discussed. In our study, TCQA and TFQA treatments in NSCs showed a significant performance on improving synapse growth and neurogenesis compared with no treatment of NSCs. The two treatments in NSCs also had a significant activation of the ErbB signaling pathway, protein kinase B (AKT), and mitogen-activated protein kinase (MAPK) kinases. In particular, the TCQA-expressed proliferation gene myelocytomatosis oncogene (Myc) had the greatest connections significantly. TFQA treatment remarkably regulated the differentiation gene jun proto-oncogene (Jun), which was the gene with greatest direct relations, while Myc was also induced in TFQA treatment. In the overall quantitative real-time polymerase chain reaction (PCR) assay, TFQA had more outstanding neural proliferation and differentiation capabilities than TCQA in NSCs. Our study suggests that TFQA has greater therapeutic potential in neurogenesis promotion and neurodegenerative diseases compared with TCQA.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11487612/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337259","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}

引用次数: 0

Comparison of Neurogenesis Promotion Effects between Cinnamoylquinic Acids in Neural Stem Cells from Adult Mice Brains 比较肉桂酰奎宁酸对成年小鼠脑神经干细胞神经发生的促进作用

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-09-30 DOI: 10.1021/acschemneuro.4c0032910.1021/acschemneuro.4c00329

Hongyu Lin, Kazunori Sasaki, Farhana Ferdousi and Hiroko Isoda*,

{"title":"Comparison of Neurogenesis Promotion Effects between Cinnamoylquinic Acids in Neural Stem Cells from Adult Mice Brains","authors":"Hongyu Lin, Kazunori Sasaki, Farhana Ferdousi and Hiroko Isoda*, ","doi":"10.1021/acschemneuro.4c0032910.1021/acschemneuro.4c00329","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00329https://doi.org/10.1021/acschemneuro.4c00329","url":null,"abstract":"Caffeoylquinic acids (CQAs) and feruloylquinic acids (FQAs), as cinnamoylquinic acids, have neurogenesis promotion effects. We studied for the first time the neurogenesis-enhancing effect of 3,4,5-tri-feruloylquinic acid (TFQA) compared to 3,4,5-tri-caffeoylquinic acid (TCQA), which has a similar structure, and explored their different cellular and molecular mechanisms in neural stem cells (NSCs) of mice brains. After 2 weeks of incubation, we first assessed the number and size of NSCs in TCQA and TFQA treatments. In NSCs treated for TCQA and TFQA, the NSC proliferation gene expression as well as neuronal and glial cell differentiation gene expressions improved. In the microarray assay, the erythroblastic oncogene B (ErbB) signaling pathway, as the common signaling of TCQA and TFQA treatments, was focused on and discussed. In our study, TCQA and TFQA treatments in NSCs showed a significant performance on improving synapse growth and neurogenesis compared with no treatment of NSCs. The two treatments in NSCs also had a significant activation of the ErbB signaling pathway, protein kinase B (AKT), and mitogen-activated protein kinase (MAPK) kinases. In particular, the TCQA-expressed proliferation gene myelocytomatosis oncogene (Myc) had the greatest connections significantly. TFQA treatment remarkably regulated the differentiation gene jun proto-oncogene (Jun), which was the gene with greatest direct relations, while Myc was also induced in TFQA treatment. In the overall quantitative real-time polymerase chain reaction (PCR) assay, TFQA had more outstanding neural proliferation and differentiation capabilities than TCQA in NSCs. Our study suggests that TFQA has greater therapeutic potential in neurogenesis promotion and neurodegenerative diseases compared with TCQA.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acschemneuro.4c00329","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142437585","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}

引用次数: 0

Fecal Microbiota Transplantation-Mediated Rebalancing of the Gut-Brain Axis Alleviates Cisplatin-Induced Neuropathic Pain. 通过粪便微生物群移植重新平衡肠脑轴可缓解顺铂诱发的神经性疼痛

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-09-27 DOI: 10.1021/acschemneuro.4c00267

Mousmi Rani, Akhilesh, Deepak Chouhan, Ankit Uniyal, Vinod Tiwari

{"title":"Fecal Microbiota Transplantation-Mediated Rebalancing of the Gut-Brain Axis Alleviates Cisplatin-Induced Neuropathic Pain.","authors":"Mousmi Rani, Akhilesh, Deepak Chouhan, Ankit Uniyal, Vinod Tiwari","doi":"10.1021/acschemneuro.4c00267","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00267","url":null,"abstract":"Chemotherapy-induced neuropathic pain (CINP) presents a significant challenge in cancer treatment, necessitating novel therapeutic approaches. The intricate relationship between CINP and the gut-brain axis indicates a crucial role for the gut microbiota in pain modulation during cancer therapy. In this study, we investigated the effect of gut microbiota and their modulation on CINP in rats. Cisplatin administration (20 mg/kg, ip) disrupted the integrity of the blood-spinal cord barrier, as evidenced by reduced expression of tight junction proteins occludin and claudin-5 and increased leakage of pro-inflammatory cytokines into the spinal cord. Fecal microbiota transplantation (FMT, 0.5 mL of P.O.) from healthy rats over 21 days restored barrier integrity, as confirmed by Evan's blue assay. FMT intervention halted the progression of cisplatin-induced pain, demonstrated through a battery of pain assays assessing mechanical, thermal, and cold allodynia alongside hyperalgesia measurements. Additionally, FMT treatment reduced oxidative stress and modulated neuro-inflammatory markers, resulting in a rebalanced cytokine profile with decreased levels of neuro-inflammatory cytokines (IL-6 and TNFα) and increased expression of the anti-inflammatory cytokine IL-10. Gut microbiota-mediated IL-1β/NF-κB signaling emerged as a critical factor in leukocyte recruitment and microglial activation, highlighting the gut-brain axis as a key regulatory nexus in managing cisplatin-induced neuropathic pain. These findings underscore the therapeutic potential of targeting gut microbiota modulation as a promising strategy for alleviating CINP and improving the well-being of cancer patients undergoing chemotherapy.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337262","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

Fecal Microbiota Transplantation-Mediated Rebalancing of the Gut–Brain Axis Alleviates Cisplatin-Induced Neuropathic Pain 通过粪便微生物群移植重新平衡肠脑轴可缓解顺铂诱发的神经性疼痛

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-09-27 DOI: 10.1021/acschemneuro.4c0026710.1021/acschemneuro.4c00267

Mousmi Rani, Akhilesh, Deepak Chouhan, Ankit Uniyal and Vinod Tiwari*,

{"title":"Fecal Microbiota Transplantation-Mediated Rebalancing of the Gut–Brain Axis Alleviates Cisplatin-Induced Neuropathic Pain","authors":"Mousmi Rani,  Akhilesh, Deepak Chouhan, Ankit Uniyal and Vinod Tiwari*, ","doi":"10.1021/acschemneuro.4c0026710.1021/acschemneuro.4c00267","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00267https://doi.org/10.1021/acschemneuro.4c00267","url":null,"abstract":"Chemotherapy-induced neuropathic pain (CINP) presents a significant challenge in cancer treatment, necessitating novel therapeutic approaches. The intricate relationship between CINP and the gut–brain axis indicates a crucial role for the gut microbiota in pain modulation during cancer therapy. In this study, we investigated the effect of gut microbiota and their modulation on CINP in rats. Cisplatin administration (20 mg/kg, ip) disrupted the integrity of the blood-spinal cord barrier, as evidenced by reduced expression of tight junction proteins occludin and claudin-5 and increased leakage of pro-inflammatory cytokines into the spinal cord. Fecal microbiota transplantation (FMT, 0.5 mL of P.O.) from healthy rats over 21 days restored barrier integrity, as confirmed by Evan’s blue assay. FMT intervention halted the progression of cisplatin-induced pain, demonstrated through a battery of pain assays assessing mechanical, thermal, and cold allodynia alongside hyperalgesia measurements. Additionally, FMT treatment reduced oxidative stress and modulated neuro-inflammatory markers, resulting in a rebalanced cytokine profile with decreased levels of neuro-inflammatory cytokines (IL-6 and TNFα) and increased expression of the anti-inflammatory cytokine IL-10. Gut microbiota-mediated IL-1β/NF-κB signaling emerged as a critical factor in leukocyte recruitment and microglial activation, highlighting the gut–brain axis as a key regulatory nexus in managing cisplatin-induced neuropathic pain. These findings underscore the therapeutic potential of targeting gut microbiota modulation as a promising strategy for alleviating CINP and improving the well-being of cancer patients undergoing chemotherapy.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142437427","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

Decoding the Role of Nuclear Sirtuins in Parkinson’s Pathogenesis 解码核 Sirtuins 在帕金森病发病机制中的作用

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-09-27 DOI: 10.1021/acschemneuro.4c0050710.1021/acschemneuro.4c00507

Dishank Patel, Ritu Soni and Jigna Shah*,

引用次数: 0

Decoding the Role of Nuclear Sirtuins in Parkinson's Pathogenesis. 解码核 Sirtuins 在帕金森病发病机制中的作用。

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-09-27 DOI: 10.1021/acschemneuro.4c00507

Dishank Patel, Ritu Soni, Jigna Shah

引用次数: 0

Blocking α₁ Adrenergic Receptor as a Novel Target for Treating Alzheimer's Disease. 将阻断α1肾上腺素能受体作为治疗阿尔茨海默病的新靶点

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-09-26 DOI: 10.1021/acschemneuro.4c00411

Xidong Pan, Zhifeng Lei, Jiang Chen, Congcong Jia, Jie Deng, Ying Liu, Xingmei Luo, Likun Wang, Dan Zi, Zhen Wang, Song Li, Jun Tan

{"title":"Blocking α1 Adrenergic Receptor as a Novel Target for Treating Alzheimer's Disease.","authors":"Xidong Pan, Zhifeng Lei, Jiang Chen, Congcong Jia, Jie Deng, Ying Liu, Xingmei Luo, Likun Wang, Dan Zi, Zhen Wang, Song Li, Jun Tan","doi":"10.1021/acschemneuro.4c00411","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00411","url":null,"abstract":"While amyloidopathy and tauopathy have been recognized as hallmarks in Alzheimer's disease (AD) brain, recently, increasing lines of evidence have supported the pathological roles of cerebrovascular changes in the pathogenesis and progression of AD. Restoring or ameliorating the impaired cerebrovascular function during the early phase of the disease may yield benefits against the cognitive decline in AD. In the present study, we evaluated the potential therapeutic effects of nicergoline [NG, a well-known α1 adrenergic receptor (ADR) blocker and vasodilator] against AD through ameliorating vascular abnormalities. Our in vitro data revealed that NG could reverse β-amyloid1-42 (Aβ1-42)-induced PKC/ERK1/2 activation, the downstream pathway of α1-ADR activation, in α1-ADR-overexpressed N2a cells. NG also blocked Aβ1-42- or phenylephrine-induced constrictions in isolated rat arteries. All these in vitro data may suggest ADR-dependent impacts of Aβ on vascular function and the reversal effect of NG. In addition, the ameliorating impacts of NG treatment on cerebral vasoconstriction, vasoremodeling, and cognitive decline were investigated in vivo in a PSAPP transgenic AD mouse model. Consistent with in vitro findings, the chronic treatment of NG significantly ameliorated the cerebrovascular dysfunctions and Aβ plaque depositions in the brain. Moreover, an improved cognitive performance was also observed. Taken together, our findings supported the beneficial effects of NG on AD through adrenergic-related mechanisms and highlighted the therapeutic potential of α1-adrenergic vasomodulators against AD pathologies.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337258","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

Blocking α1 Adrenergic Receptor as a Novel Target for Treating Alzheimer’s Disease 将阻断α1肾上腺素能受体作为治疗阿尔茨海默病的新靶点

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-09-26 DOI: 10.1021/acschemneuro.4c0041110.1021/acschemneuro.4c00411

Xidong Pan, Zhifeng Lei, Jiang Chen, Congcong Jia, Jie Deng, Ying Liu, Xingmei Luo, Likun Wang, Dan Zi, Zhen Wang*, Song Li* and Jun Tan*,

{"title":"Blocking α1 Adrenergic Receptor as a Novel Target for Treating Alzheimer’s Disease","authors":"Xidong Pan, Zhifeng Lei, Jiang Chen, Congcong Jia, Jie Deng, Ying Liu, Xingmei Luo, Likun Wang, Dan Zi, Zhen Wang*, Song Li* and Jun Tan*, ","doi":"10.1021/acschemneuro.4c0041110.1021/acschemneuro.4c00411","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00411https://doi.org/10.1021/acschemneuro.4c00411","url":null,"abstract":"While amyloidopathy and tauopathy have been recognized as hallmarks in Alzheimer’s disease (AD) brain, recently, increasing lines of evidence have supported the pathological roles of cerebrovascular changes in the pathogenesis and progression of AD. Restoring or ameliorating the impaired cerebrovascular function during the early phase of the disease may yield benefits against the cognitive decline in AD. In the present study, we evaluated the potential therapeutic effects of nicergoline [NG, a well-known α1 adrenergic receptor (ADR) blocker and vasodilator] against AD through ameliorating vascular abnormalities. Our in vitro data revealed that NG could reverse β-amyloid1–42 (Aβ1–42)-induced PKC/ERK1/2 activation, the downstream pathway of α1-ADR activation, in α1-ADR-overexpressed N2a cells. NG also blocked Aβ1–42- or phenylephrine-induced constrictions in isolated rat arteries. All these in vitro data may suggest ADR-dependent impacts of Aβ on vascular function and the reversal effect of NG. In addition, the ameliorating impacts of NG treatment on cerebral vasoconstriction, vasoremodeling, and cognitive decline were investigated in vivo in a PSAPP transgenic AD mouse model. Consistent with in vitro findings, the chronic treatment of NG significantly ameliorated the cerebrovascular dysfunctions and Aβ plaque depositions in the brain. Moreover, an improved cognitive performance was also observed. Taken together, our findings supported the beneficial effects of NG on AD through adrenergic-related mechanisms and highlighted the therapeutic potential of α1-adrenergic vasomodulators against AD pathologies.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142437470","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

Glycation Produces Topologically Different α-Synuclein Oligomeric Strains and Modulates Microglia Response via the NLRP3-Inflammasome Pathway. 糖化产生拓扑结构不同的α-突触核蛋白寡聚体菌株，并通过 NLRP3-炎症小体途径调节小胶质细胞的反应

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-09-25 DOI: 10.1021/acschemneuro.4c00057

Manisha Kumari, Krishna Singh Bisht, Kriti Ahuja, Rajender K Motiani, Tushar Kanti Maiti

{"title":"Glycation Produces Topologically Different α-Synuclein Oligomeric Strains and Modulates Microglia Response via the NLRP3-Inflammasome Pathway.","authors":"Manisha Kumari, Krishna Singh Bisht, Kriti Ahuja, Rajender K Motiani, Tushar Kanti Maiti","doi":"10.1021/acschemneuro.4c00057","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00057","url":null,"abstract":"α-Synuclein, a key player in Parkinson's disease and other synucleinopathies, possesses an inherently disordered structure that allows for versatile structural changes during aggregation. Microglia, the brain immune cells, respond differently to various α-synuclein strains, influencing their activation and release of harmful molecules, leading to neuronal death. Post-translational modifications, such as glycation in α-synuclein, add a layer of complexity to microglial activation. This study aimed to explore the impact of glycation on α-synuclein aggregation and microglial responses, which have not been studied before. Biophysical analyses revealed that glycated α-synuclein oligomers had distinct morphologies with a more negative and hydrophobic surface, preventing fibril formation and interfering with membrane interactions. Notably, there was increased cytosolic Ca2+ dysregulation, redox stress, and mitochondrial instability compared to cells exposed to unmodified α-synuclein oligomers. Additionally, glycated α-synuclein oligomers exhibited impaired binding to Toll-like receptor 2, compromising downstream signaling. Surprisingly, these oligomers promoted TLR4 endocytosis and degradation. In our experiments with oligomers, glycated α-synuclein oligomers preferred NLRP3 inflammasome-mediated neuroinflammation, contributing differently from unmodified α-synuclein oligomers. In summary, this study unveils the mechanism underlying the effect of glycation on α-synuclein oligomers and highlights the conformation-specific microglial responses toward extracellular α-synuclein.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337263","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