ASN NEURO最新文献_第3页

The CEMIP Hyaluronidase is Elevated in Oligodendrocyte Progenitor Cells and Inhibits Oligodendrocyte Maturation. 少突胶质细胞祖细胞中CEMIP透明质酸酶升高并抑制少突胶质细胞成熟。

IF 3.7 4区医学

ASN NEURO Pub Date : 2025-01-01 Epub Date: 2025-12-08 DOI: 10.1080/17590914.2025.2600157

Alec Peters, Kanon Yasuhara, Weiping Su, Steven Matsumoto, Peter Pham, Fatima Banine, Eliana Harris, Stephen A Back, Larry S Sherman

{"title":"The CEMIP Hyaluronidase is Elevated in Oligodendrocyte Progenitor Cells and Inhibits Oligodendrocyte Maturation.","authors":"Alec Peters, Kanon Yasuhara, Weiping Su, Steven Matsumoto, Peter Pham, Fatima Banine, Eliana Harris, Stephen A Back, Larry S Sherman","doi":"10.1080/17590914.2025.2600157","DOIUrl":"10.1080/17590914.2025.2600157","url":null,"abstract":"Central nervous system (CNS) demyelination occurs in numerous conditions including multiple sclerosis (MS). CNS remyelination involves recruitment and maturation of oligodendrocyte progenitor cells (OPCs). Remyelination often fails in part due to the inhibition of OPC maturation into myelinating oligodendrocytes (OLs). Digestion products of the glycosaminoglycan hyaluronan (HA), generated by hyaluronidase activity, block OPC maturation and remyelination. Here, we aimed to identify which hyaluronidases are elevated in demyelinating lesions and to test if they influence OPC maturation and remyelination. We find that the Cell Migration Inducing and hyaluronan binding Protein (CEMIP) is elevated in demyelinating lesions in mice with experimental autoimmune encephalomyelitis during peak disease when neuroinflammatory mediators, including tumor necrosis factor-α (TNFα), are at high levels. CEMIP expression is also elevated in demyelinated MS patient lesions. CEMIP is expressed by OPCs, and TNFα induces increased CEMIP expression by OPCs. Both increased CEMIP expression and HA fragments generated by CEMIP block OPC maturation into OLs. CEMIP-derived HA fragments also prevent remyelination in vivo. These data indicate that CEMIP blocks remyelination by generating bioactive HA fragments that inhibit OPC maturation. CEMIP is therefore a potential target for therapies aimed at promoting remyelination.","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"17 1","pages":"2600157"},"PeriodicalIF":3.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12694905/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145707169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

A Brain Endothelial Cell Caveolin-1/CXCL10 Axis Promotes T Cell Transcellular Migration Across the Blood-Brain Barrier. 脑内皮细胞小窝蛋白-1/CXCL10轴促进T细胞跨血脑屏障的细胞迁移

IF 3.7 4区医学

ASN NEURO Pub Date : 2025-01-01 Epub Date: 2025-03-10 DOI: 10.1080/17590914.2025.2472070

Troy N Trevino, Ali A Almousawi, Remy Martins-Goncalves, Andrea Ochoa-Raya, KaReisha F Robinson, Genesis L Abad, Leon M Tai, Suellen D Oliveira, Richard D Minshall, Sarah E Lutz

{"title":"A Brain Endothelial Cell Caveolin-1/CXCL10 Axis Promotes T Cell Transcellular Migration Across the Blood-Brain Barrier.","authors":"Troy N Trevino, Ali A Almousawi, Remy Martins-Goncalves, Andrea Ochoa-Raya, KaReisha F Robinson, Genesis L Abad, Leon M Tai, Suellen D Oliveira, Richard D Minshall, Sarah E Lutz","doi":"10.1080/17590914.2025.2472070","DOIUrl":"10.1080/17590914.2025.2472070","url":null,"abstract":"The mechanisms that govern whether T cells cross blood-brain barrier (BBB) endothelium by transcellular versus paracellular routes are unclear. Caveolin-1 is a membrane scaffolding and signaling protein associated with transcellular transmigration through the endothelial cytoplasm. Here, we report that the neuroinflammatory chemokine CXCL10 induced transcellular, caveolar transmigration of CXCR3+ CD4+ T cells. Specifically, data revealed that CXCL10-induced transcellular transmigration requires expression of Caveolin-1 and ICAM-1 in brain endothelial cells and of the CXCL10 receptor, CXCR3, and LFA-1 in T cells. Moreover, Caveolin-1 promoted CXCL10 aggregation into brain endothelial cytoplasmic stores, providing a mechanism for activation and recruitment of CXCR3+ T cells to migrate at cytoplasmic locations, distal to cell-cell junctions. Consistent with our in vitro data, genetic ablation of Caveolin-1 reduces infiltration of CXCR3+ CD4+ T cells into the CNS in experimental autoimmune encephalomyelitis. Our findings establish a novel mechanism by which brain endothelial cells utilize Caveolin-1 dependent CXCL10 intracellular stores to license T cells for transcellular migration across the blood-brain barrier.","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"17 1","pages":"2472070"},"PeriodicalIF":3.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12047051/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143596193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Sex Affects Cognitive Outcomes in HIV-1 Tat Transgenic Mice: Role of CCR5. 性别影响HIV-1 Tat转基因小鼠的认知结果：CCR5的作用

IF 3.7 4区医学

ASN NEURO Pub Date : 2025-01-01 Epub Date: 2025-01-13 DOI: 10.1080/17590914.2024.2447338

Chloe A Simons, Sarah Kim, Yun K Hahn, Ama Boake-Agyei, Sara R Nass, Phu Vo, Kurt F Hauser, Pamela E Knapp

{"title":"Sex Affects Cognitive Outcomes in HIV-1 Tat Transgenic Mice: Role of CCR5.","authors":"Chloe A Simons, Sarah Kim, Yun K Hahn, Ama Boake-Agyei, Sara R Nass, Phu Vo, Kurt F Hauser, Pamela E Knapp","doi":"10.1080/17590914.2024.2447338","DOIUrl":"10.1080/17590914.2024.2447338","url":null,"abstract":"People living with HIV (PLWH) experience HIV-associated neurocognitive disorders (HAND), even though combination antiretroviral therapy (cART) suppresses HIV replication. HIV-1 transactivator of transcription (HIV-1 Tat) contributes to the development of HAND through neuroinflammatory and neurotoxic mechanisms. C-C chemokine 5 receptor (CCR5) is important in immune cell targeting and is a co-receptor for HIV viral entry into CD4+ cells. Notably, CCR5 has been implicated in cognition unrelated to HIV infection. Inhibition of CCR5 has been shown to improve learning and memory. To test whether CCR5 is involved in cognitive changes in HAND, we used a non-infectious, transgenic model in which HIV-1 Tat is inducibly expressed. Well-powered cohorts of male and female mice were placed on a diet containing doxycycline to induce Tat expression for 8-wks. Males showed Tat-mediated deficits in the Barnes maze test of spatial learning and memory; females showed no impairments. Deficits in the males were fully reversed by the CCR5 antagonist, maraviroc (MVC). Tat-mediated deficits were not found in novel object recognition or contextual fear conditioning in either sex. Based on earlier work, we hypothesized that MVC might increase brain-derived neurotrophic factor (BDNF), which is essential in maintaining synaptodendritic function. MVC did increase the mBDNF to proBDNF ratio in males, perhaps contributing to improved cognition.","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"17 1","pages":"2447338"},"PeriodicalIF":3.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11877617/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142977399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

P-glycoprotein and Alzheimer's Disease: Threats and Opportunities. p -糖蛋白与阿尔茨海默病：威胁与机遇。

IF 3.7 4区医学

ASN NEURO Pub Date : 2025-01-01 Epub Date: 2025-04-23 DOI: 10.1080/17590914.2025.2495632

Joseph Jr Asante, Steven W Barger

{"title":"P-glycoprotein and Alzheimer's Disease: Threats and Opportunities.","authors":"Joseph Jr Asante, Steven W Barger","doi":"10.1080/17590914.2025.2495632","DOIUrl":"10.1080/17590914.2025.2495632","url":null,"abstract":"Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects more than 50 million people worldwide. One of the hallmark features of AD is the accumulation of amyloid β-peptide (Aβ) protein in the brain. P-glycoprotein (P-gp) is a membrane-bound protein expressed in various tissues, including the cerebrovascular endothelium. It plays a crucial role in the efflux of toxic substances, including Aβ, from the brain. Aberrations in P-gp levels or activity have been implicated in the pathogenesis of AD by promoting the accumulation of Aβ in the brain. Therefore, modulating the P-gp function represents a promising therapeutic strategy for treating AD. P-gp has multiple substrate binding sites, creating the potential for substrates to fall into complementation groups based on these sites; two substrates in the same complementation group may compete with one other, but two substrates in different groups may exhibit cooperativity. Thus, a given P-gp substrate may interfere with Aβ efflux whereas another may promote clearance. These threats and opportunities, as well as other aspects of P-gp relevance to AD, are discussed here.","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"17 1","pages":"2495632"},"PeriodicalIF":3.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12140463/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Proliferating Microglia Exhibit Unique Transcriptional and Functional Alterations in Alzheimer's Disease. 增生性小胶质细胞在阿尔茨海默病中表现出独特的转录和功能改变。

IF 3.7 4区医学

ASN NEURO Pub Date : 2025-01-01 Epub Date: 2025-05-19 DOI: 10.1080/17590914.2025.2506406

Nàdia Villacampa, Heela Sarlus, Paula Martorell, Khushbu Bhalla, Sergio Castro-Gomez, Ana Vieira-Saecker, Ilya Slutzkin, Kristian Händler, Carmen Venegas, Róisín McManus, Thomas Ulas, Marc Beyer, Eran Segal, Michael T Heneka

{"title":"Proliferating Microglia Exhibit Unique Transcriptional and Functional Alterations in Alzheimer's Disease.","authors":"Nàdia Villacampa, Heela Sarlus, Paula Martorell, Khushbu Bhalla, Sergio Castro-Gomez, Ana Vieira-Saecker, Ilya Slutzkin, Kristian Händler, Carmen Venegas, Róisín McManus, Thomas Ulas, Marc Beyer, Eran Segal, Michael T Heneka","doi":"10.1080/17590914.2025.2506406","DOIUrl":"10.1080/17590914.2025.2506406","url":null,"abstract":"Proliferation of microglia represents a physiological process, which is accelerated in several neurodegenerative disorders including Alzheimer disease (AD). The effect of such neurodegeneration-associated microglial proliferation on function and disease progression remains unclear. Here, we show that proliferation results in profound alterations of cellular function by providing evidence that newly proliferated microglia show impaired beta-amyloid clearance in vivo. Through sorting of proliferating microglia of APP/PS1 mice and subsequent transcriptome analysis, we define unique proliferation-associated transcriptomic signatures that change with age and beta-amyloid accumulation and are characterized by enrichment of immune system-related pathways. Of note, we identify the DEAD-Box Helicase 3 X-Linked (DDX3X) as a key molecule to modulate microglia activation and cytokine secretion and it is expressed in the AD brain. Together, these results argue for a novel concept by which phenotypic and functional microglial changes occur longitudinally as a response to accelerated proliferation in a neurodegenerative environment.","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"17 1","pages":"2506406"},"PeriodicalIF":3.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12140498/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Combined Treatment with Minocycline and an mGluR5 Antagonist Alters Resting EEG Spectral Power, but Not Sound-Evoked Responses, in a Mouse Model of Fragile X Syndrome. 米诺环素和mGluR5拮抗剂联合治疗可改变脆性X综合征小鼠模型的静息脑电图谱功率，但不会改变声音诱发反应。

IF 3.7 4区医学

ASN NEURO Pub Date : 2025-01-01 Epub Date: 2025-10-16 DOI: 10.1080/17590914.2025.2564628

M H Kassir, J W Lovelace, D K Binder, I E Ethell, K A Razak

{"title":"Combined Treatment with Minocycline and an mGluR5 Antagonist Alters Resting EEG Spectral Power, but Not Sound-Evoked Responses, in a Mouse Model of Fragile X Syndrome.","authors":"M H Kassir, J W Lovelace, D K Binder, I E Ethell, K A Razak","doi":"10.1080/17590914.2025.2564628","DOIUrl":"10.1080/17590914.2025.2564628","url":null,"abstract":"Fragile X Syndrome (FXS) is a leading genetic cause of intellectual disability and autism-like behaviors. Glutamatergic mGluR5 receptors and matrix metalloproteinase-9 (MMP-9) are therapeutic targets to treat FXS, but clinical trials targeting each of these pathways have not been successful. Here, we tested if the electroencephalography (EEG) phenotypes associated with FXS are reversed with a novel combination of treatments affecting the two pathways. Fmr1 knockout (KO) mice were given 10 days of CTEP (mGluR5 antagonist) alone or in combination with minocycline (MMP-9 inhibitor). EEG was recorded during resting (no acoustic stimulation) and during sound presentations (to produce sound-evoked EEG) at 1 day and 10 days after the beginning of treatment administration to test acute effects and potential tachyphylaxis. In pre-treatment WT and KO mice comparisons, we replicated previously published Fmr1 KO mouse EEG phenotypes including elevated power in the resting gamma band, elevated single trial power, and reduced phase-locking to spectrotemporally dynamic auditory stimuli. We found that CTEP treatment alone did not show any benefit compared to vehicle in Fmr1 KO mice after either 1 or 10 days of treatment. CTEP + minocycline reduced resting gamma band power in the Fmr1 KO mice to a greater extent than vehicle at both treatment time points. There were no effects on sound-evoked responses. These data suggest that combined CTEP and minocycline treatment alters resting EEG measures while each treatment administered separately does not yield similar changes. High power in broadband gamma frequency correlates with irritability, stereotyped behaviors, and hyperactivity in FXS patients, suggesting a combination of drugs that reduce mGluR5 and MMP-9 activity may be beneficial in FXS.","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"17 1","pages":"2564628"},"PeriodicalIF":3.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12533955/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145298505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Identifying Lanthionine Ketimine Derivatives for Maturation and Proliferative Effects in Oligodendrocyte Progenitor Cells. 鉴定少突胶质细胞祖细胞成熟和增殖作用的硫代氨酸酮衍生物。

IF 3.7 4区医学

ASN NEURO Pub Date : 2025-01-01 Epub Date: 2025-07-21 DOI: 10.1080/17590914.2025.2535963

Zachary McDonald, Ankit Tandon, Travis T Denton, Mehek Taneja, Jacqueline Rocha, Jeffrey L Dupree, Pablo M Paez, Veronica T Cheli, Swathi G Tumuluri, Douglas L Feinstein

{"title":"Identifying Lanthionine Ketimine Derivatives for Maturation and Proliferative Effects in Oligodendrocyte Progenitor Cells.","authors":"Zachary McDonald, Ankit Tandon, Travis T Denton, Mehek Taneja, Jacqueline Rocha, Jeffrey L Dupree, Pablo M Paez, Veronica T Cheli, Swathi G Tumuluri, Douglas L Feinstein","doi":"10.1080/17590914.2025.2535963","DOIUrl":"10.1080/17590914.2025.2535963","url":null,"abstract":"Previous studies have shown that lanthionine ketimine ethyl ester (LKE) reduces clinical scores in the experimental autoimmune encephalomyelitis (EAE) mouse model of Multiple Sclerosis, induces differentiation of oligodendrocyte progenitor cells (OPCs) in vitro, and accelerates remyelination following cuprizone induced demyelination. In a search for derivatives with greater efficacy to induce OPC maturation or proliferation, we screened a panel of 2-alkyl and 3-phosphonate substituted LK derivatives. Incubation of Oli-neu oligodendrocyte cells with 2-n-butyl- or 2-n-hexyl-LKE-phosphonate reduced spontaneous cell death, increased proliferation, and increased maturation. These were associated with changes in corresponding mRNA levels of Olig2, PLP, and O4. These derivatives also reduced cell death and increased proliferation and maturation in primary mouse OPCs. The increased hydrophobicity of these derivatives suggests these will be better candidates for testing effects in animal models of Multiple Sclerosis and other demyelinating diseases.","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"17 1","pages":"2535963"},"PeriodicalIF":3.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12296138/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144681923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Assessment of Phase-Dependent Alterations in Cortical Glycolytic and Mitochondrial Metabolism Following Ischemic Stroke. 缺血性脑卒中后皮质糖酵解和线粒体代谢阶段依赖性改变的评估。

IF 3.7 4区医学

ASN NEURO Pub Date : 2025-01-01 Epub Date: 2025-04-10 DOI: 10.1080/17590914.2025.2488935

Shokofeh Rahimpour, Ethan Meadows, John M Hollander, Kate Karelina, Candice M Brown

{"title":"Assessment of Phase-Dependent Alterations in Cortical Glycolytic and Mitochondrial Metabolism Following Ischemic Stroke.","authors":"Shokofeh Rahimpour, Ethan Meadows, John M Hollander, Kate Karelina, Candice M Brown","doi":"10.1080/17590914.2025.2488935","DOIUrl":"10.1080/17590914.2025.2488935","url":null,"abstract":"Maintaining optimal brain metabolism supports neuronal function, synaptic communication, and cognitive processes. During ischemic stroke, brain metabolism and cellular bioenergetics within the neurovascular unit are disrupted, emphasizing the significance of understanding the physiology and pathology of the stroke brain. The objective of this study was to quantify and compare phase-dependent changes in glycolysis and oxidative phosphorylation following ischemic stroke by using the Seahorse XFe24 Analyzer. Since there are limited established methods to quantify glycolytic activity in brain tissue, we optimized the accuracy and reproducibility of extracellular acidification rate (ECAR) measurement by increasing the incubation time following exposure to each reagent. Following optimization, we quantified both ECAR and the oxygen consumption rate (OCR), a measure of oxidative phosphorylation, in cortical brain tissue punches corresponding to the penumbra from mice subjected to ischemic stroke. ECAR and OCR were quantified in tissue punches from the injured (ipsilateral) and the non-injured (contralateral) hemispheres at 48 hours, 7 days, and 14 days post-stroke. Normalized ECAR measurements showed elevated glycolytic activity in the ipsilateral and contralateral hemispheres at 7 days post-stroke compared to other time points. In contrast, normalized OCR measurements showed a modest increase in basal respiration within the ipsilateral hemispheres between 48 hours and 14 days post-stroke. In summary, the results demonstrate that ischemic stroke results in a distinct phase-dependent metabolic phenotype in both cortical hemispheres that persists up to 14 days after injury.","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"17 1","pages":"2488935"},"PeriodicalIF":3.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12140487/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143975226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Global Deficiency of Alzheimer's Disease Risk Gene Il1rap Reduces Pathological Tau in a Mouse Model of Systemic Inflammation. 在小鼠全身性炎症模型中，阿尔茨海默病风险基因Il1rap的整体缺失减少了病理性Tau

IF 3.7 4区医学

ASN NEURO Pub Date : 2025-01-01 Epub Date: 2025-12-06 DOI: 10.1080/17590914.2025.2598310

Somayeh Dadras, Kiran Bhaskar

{"title":"Global Deficiency of Alzheimer's Disease Risk Gene Il1rap Reduces Pathological Tau in a Mouse Model of Systemic Inflammation.","authors":"Somayeh Dadras, Kiran Bhaskar","doi":"10.1080/17590914.2025.2598310","DOIUrl":"10.1080/17590914.2025.2598310","url":null,"abstract":"Brain inflammation is strongly associated with neurodegeneration in Alzheimer's disease (AD) and related tauopathies. We have previously demonstrated that microglia-derived interleukin-1β (IL-1β) induces tau hyperphosphorylation in a cell-autonomous manner and depends on activating the IL-1 receptor (IL-1R1) signaling pathway. IL-1 receptor accessory protein (IL-1RAcP) is a co-receptor for IL-1R1 and is essential for the IL-1R1 receptor function and downstream signaling. Genome-wide association studies have identified several single-nucleotide polymorphisms (SNPs) in the IL1RAP gene that have been shown to increase AD risk. Here, we demonstrate that global and neuron-specific isoform deficiency of IL-1RAcP regulates hyperphosphorylated tau levels in a lipopolysaccharide (LPS)-induced mouse model of systemic inflammation. Notably, while global Il1rap-/- reduced pS202(AT8) and pT231 (AT180) tau levels, neuron-specific IL-1RAcP (IL-1RAcPb) deficiency specifically increased total tau levels. Together, these results suggest that IL-1RAcP is an important regulator of tau hyperphosphorylation relevant to AD and related tauopathies.","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"17 1","pages":"2598310"},"PeriodicalIF":3.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12688222/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145695993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Dysregulated Expression of Inflammasome and Extracellular Matrix Genes in C9orf72-ALS/FTD Microglia. C9orf72-ALS/FTD小胶质细胞中炎性小体和细胞外基质基因表达异常。

IF 3.7 4区医学

ASN NEURO Pub Date : 2025-01-01 Epub Date: 2025-08-07 DOI: 10.1080/17590914.2025.2542998

Louise Thiry, Nisha S Pulimood, Ye Man Tang, Stefano Stifani

{"title":"Dysregulated Expression of Inflammasome and Extracellular Matrix Genes in C9orf72-ALS/FTD Microglia.","authors":"Louise Thiry, Nisha S Pulimood, Ye Man Tang, Stefano Stifani","doi":"10.1080/17590914.2025.2542998","DOIUrl":"10.1080/17590914.2025.2542998","url":null,"abstract":"Hexanucleotide repeat expansion (HRE) in the non-coding region of the gene C9orf72 is the most prevalent mutation in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The C9orf72 HRE contributes to neuron degeneration in ALS/FTD through both cell-autonomous mechanisms and non-cell autonomous disease processes involving glial cells such as microglia. The molecular mechanisms underlying the contribution of C9orf72-HRE microglia to neuron death in ALS/FTD remain to be fully elucidated. In this study, we generated microglia from human C9orf72-HRE and isogenic iPSCs using three different microglia derivation methods. RNA sequencing analysis reveals a cell-autonomous dysregulation of extracellular matrix (ECM) genes and genes involved in pathways underlying inflammasome activation in C9orf72-HRE microglia. In agreement with elevated expression of inflammasome components, conditioned media from C9orf72-HRE microglia enhance the death of C9orf72-HRE motor neurons implicating microglia-secreted molecules in non-cell autonomous mechanisms of C9orf72 HRE pathology. These findings suggest that aberrant activation of inflammasome-mediated mechanisms in C9orf72-HRE microglia results in a pro-inflammatory phenotype that contributes to non-cell autonomous mechanisms of motor neuron degeneration in ALS/FTD.","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"17 1","pages":"2542998"},"PeriodicalIF":3.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12499538/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144798044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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