Neurobiology of Disease最新文献_第8页

Expression of protein disulfide isomerase A3Q481K variant associated with amyotrophic lateral sclerosis triggers disease features in mice 与肌萎缩性侧索硬化症相关的蛋白二硫异构酶A3变异的表达引发小鼠的疾病特征。

IF 5.1 2区医学

Neurobiology of Disease Pub Date : 2025-05-07 DOI: 10.1016/j.nbd.2025.106947

Martin Sepulveda , Francisca Martínez Traub , Patricia Ojeda , Viviana Perez , Jorge Ojeda , Jessica Mella , Rodrigo Diaz , Pablo Rozas , Matías Mansilla-Jaramillo , Amparo Zuleta , Guillermo Diaz , Bredford Kerr , Ute Woehlbier , Juan Pablo Henríquez , Danilo B. Medinas , Claudio Hetz

{"title":"Expression of protein disulfide isomerase A3Q481K variant associated with amyotrophic lateral sclerosis triggers disease features in mice","authors":"Martin Sepulveda , Francisca Martínez Traub , Patricia Ojeda , Viviana Perez , Jorge Ojeda , Jessica Mella , Rodrigo Diaz , Pablo Rozas , Matías Mansilla-Jaramillo , Amparo Zuleta , Guillermo Diaz , Bredford Kerr , Ute Woehlbier , Juan Pablo Henríquez , Danilo B. Medinas , Claudio Hetz","doi":"10.1016/j.nbd.2025.106947","DOIUrl":"10.1016/j.nbd.2025.106947","url":null,"abstract":"<div><div>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of motoneurons and compromised proteostasis. Dysfunction of the endoplasmic reticulum (ER) has been identified as a transversal pathogenic mechanism associated with motoneurons vulnerability in ALS. Protein disulfide isomerases (PDIs) are key enzymes catalyzing protein folding at the ER that are altered in the disease, involving biochemical and genetic perturbations. In ALS cases, we previously identified variants in the gene encoding PDIA3 (also known as Grp58 or ERp57), which were associated with altered neurite outgrowth in cell culture and abnormal motoneuron connectivity in zebrafish. Here, we report the generation of transgenic mice expressing the ALS-associated PDIA3<sup>Q481K</sup> variant. Moderate PDIA3<sup>Q481K</sup> overexpression resulted in altered motor capacity accompanied by decreased motoneuron number. The adverse effects of PDIA3<sup>Q481K</sup> expression were associated with induction of ER stress in the spinal cord and subtle morphological changes in neuromuscular junctions. Our results suggest that the PDIA3<sup>Q481K</sup> variant is likely pathogenic and its overexpression in mice recapitulate some ALS features, further supporting the concept that altered proteostasis due to PDI dysfunction may predispose an individual to develop the disease.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"212 ","pages":"Article 106947"},"PeriodicalIF":5.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144037319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Gene co-expression patterns shared between chemobrain and neurodegenerative disease models in rodents 啮齿类动物化学脑和神经退行性疾病模型之间基因共表达模式的共享

IF 5.1 2区医学

Neurobiology of Disease Pub Date : 2025-05-06 DOI: 10.1016/j.nbd.2025.106944

Mohammad-Sajad Zare , Navid Abedpoor , Fatemeh Hajibabaie , Adam K. Walker

{"title":"Gene co-expression patterns shared between chemobrain and neurodegenerative disease models in rodents","authors":"Mohammad-Sajad Zare , Navid Abedpoor , Fatemeh Hajibabaie , Adam K. Walker","doi":"10.1016/j.nbd.2025.106944","DOIUrl":"10.1016/j.nbd.2025.106944","url":null,"abstract":"<div><div>Chemotherapy-related cognitive impairment (CRCI), is a well-recognized phenomenon in cancer patients who have undergone chemotherapy but the exact molecular mechanisms underpinning CRCI remain elusive. Symptoms reported by people with CRCI resemble those experienced by people with age-related neurodegenerative disorders (ARNDDs), yet no clear connection between CRCI and ARNDDs has been reported to date. The existence of shared mechanisms between these conditions offers opportunities for repurposing drugs already approved for the treatment of ARNDDs to improve symptoms of CRCI. Given that there is no available microarray or RNA-Seq data from the brains of people who have experienced CRCI, we investigated to what extent brain gene expression perturbations from validated rodent models of CRCI induced by chemotherapy compared with validated rodent models of Alzheimer’s disease and Parkinson’s disease. We utilized multiple bioinformatic analyses, including functional enrichment, protein-protein interaction network analyses, gene ontology analyses and identification of hub genes to reveal connections between comparable gene expression perturbations observed in these conditions. Collectively 165 genes overlapped between CRCI and Parkinson’s disease and/or Alzheimer’s disease, and 15 overlapped between all three conditions. The joint genes between Alzheimer’s disease, Parkinson’s disease and CRCI demonstrate an average of 83.65% nucleotide sequence similarity to human orthologues. Gene ontology and pathway enrichment analyses suggest mechanisms involved in neural activity and inflammatory response as the key components of the studied neuropathological conditions. Accordingly, genes in which expression was comparably affected in all three condition models could be attributed to neuroinflammation, cell cycle arrest, and changes in physiological neural activity.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"211 ","pages":"Article 106944"},"PeriodicalIF":5.1,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143931988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Neuroimmune signaling mediates astrocytic nucleocytoplasmic disruptions and stress granule formation associated with TDP-43 pathology 神经免疫信号介导星形细胞核胞质破坏和与TDP-43病理相关的应激颗粒形成

IF 5.1 2区医学

Neurobiology of Disease Pub Date : 2025-05-06 DOI: 10.1016/j.nbd.2025.106939

Constance Zhou , Evelyn J. Hardin , Till S. Zimmer , Stephanie Jackvony , Daniel Barnett , Noopur Khobrekar , Elisa Giacomelli , Lorenz Studer , Adam L. Orr , Anna G. Orr

{"title":"Neuroimmune signaling mediates astrocytic nucleocytoplasmic disruptions and stress granule formation associated with TDP-43 pathology","authors":"Constance Zhou , Evelyn J. Hardin , Till S. Zimmer , Stephanie Jackvony , Daniel Barnett , Noopur Khobrekar , Elisa Giacomelli , Lorenz Studer , Adam L. Orr , Anna G. Orr","doi":"10.1016/j.nbd.2025.106939","DOIUrl":"10.1016/j.nbd.2025.106939","url":null,"abstract":"<div><div>Alterations in transactivating response region DNA-binding protein 43 (TDP-43) are prevalent in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurological disorders. TDP-43 influences neuronal functions and might also affect glial cells. However, specific intracellular effects of TDP-43 alterations on glial cells and underlying mechanisms are not clear. We report that TDP-43 dysregulation in mouse and human cortical astrocytes causes nucleoporin mislocalization, nuclear envelope remodeling, and changes in nucleocytoplasmic protein transport. These effects are dependent on interleukin-1 (IL-1) receptor activity and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling and are associated with the formation of cytoplasmic stress granules. Stimulation of IL-1 receptors and NF-κB signaling are necessary and sufficient to induce astrocytic stress granules and rapid nucleocytoplasmic changes, which are broadly alleviated by inhibition of the integrated stress response. These findings establish that TDP-43 alterations and neuroimmune factors can induce nucleocytoplasmic changes through NF-κB signaling, revealing mechanistic convergence of proteinopathy and neuroimmune pathways onto glial nucleocytoplasmic disruptions that may occur in diverse neurological conditions.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"211 ","pages":"Article 106939"},"PeriodicalIF":5.1,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143928255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Circadian disruption upon painful peripheral nerve injury in mice: Temporal effects on transcriptome in pain-regulating sensory tissues 小鼠疼痛周围神经损伤的昼夜节律中断：疼痛调节感觉组织转录组的时间效应

IF 5.1 2区医学

Neurobiology of Disease Pub Date : 2025-05-03 DOI: 10.1016/j.nbd.2025.106934

Wenjing Dai , Manqing Wen , Eija Kalso , Vinko Palada

{"title":"Circadian disruption upon painful peripheral nerve injury in mice: Temporal effects on transcriptome in pain-regulating sensory tissues","authors":"Wenjing Dai , Manqing Wen , Eija Kalso , Vinko Palada","doi":"10.1016/j.nbd.2025.106934","DOIUrl":"10.1016/j.nbd.2025.106934","url":null,"abstract":"<div><h3>Background</h3><div>Neuropathic pain (NP) resulting from nerve damage shows diurnal fluctuation of intensity in patients, indicating circadian regulation. However, mechanisms linking NP and circadian regulation remain unclear. This study aimed to investigate time-dependent transcriptomic changes during a 24-hour period using a spared nerve injury (SNI) mouse model of NP.</div></div><div><h3>Methods</h3><div>Pain-related behaviours were assessed at baseline and on days 7, 14, and 21 after SNI and control sham surgeries in C57BL/6JRJ mice. Spinal cord (SC) and periaqueductal gray (PAG) were collected 4-hourly over 24 h upon completion of behavioural testing.</div></div><div><h3>Results</h3><div>RNA sequencing revealed 111 up- and 21 downregulated differentially expressed genes (DEGs) in the SC, and 35 up- and 33 downregulated DEGs in the PAG, across all six time points. The large majority of DEGs, 245 in the SC and 191 in the PAG, are involved in regulation of immunity. Among the top expressed genes, five DEGs in the SC, <em>Atf3</em>, <em>Anxa10</em>, <em>Gpr151</em>, <em>Cxcl10</em>, <em>Sprr1a</em>, and two DEGs in the PAG, <em>Igf2</em> and <em>Wnt6</em>, were previously reported to regulate pain. Circadian analysis using CircaCompare identified 383 SC transcripts and 261 PAG transcripts with altered rhythmicity. Variability of gene expression during circadian day was increased in the SC and decreased in the PAG from the SNI mice.</div></div><div><h3>Conclusion</h3><div>These findings suggest that NP disrupts the circadian expression of rhythmic transcripts in the SC and PAG, potentially revealing new targets for chronotherapy of NP.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"211 ","pages":"Article 106934"},"PeriodicalIF":5.1,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143907472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Retraction Notice to “LRRK2 kinase activity mediates toxic interactions between genetic mutation and oxidative stress in a Drosophila model: Suppression by curcumin” [Neurobiology of Disease 47 (2012) 385–392] “在果蝇模型中，LRRK2激酶活性介导基因突变和氧化应激之间的毒性相互作用：姜黄素的抑制作用”[Neurobiology of Disease 47 (2012) 385-392]

IF 5.1 2区医学

Neurobiology of Disease Pub Date : 2025-05-03 DOI: 10.1016/j.nbd.2025.106930

Dejun Yang , Tianxia Li , Zhaohui Liu , Nicolas Arbez , Jianqun Yan , Timothy H. Moran , Christopher A. Ross , Wanli W. Smith

引用次数: 0

Serotonin innervation of the subthalamic nucleus in parkinsonian monkeys 帕金森猴丘脑下核的血清素神经支配

IF 5.1 2区医学

Neurobiology of Disease Pub Date : 2025-05-02 DOI: 10.1016/j.nbd.2025.106938

C.V.L. Delmas , J. Munro , M. Bérard , T. Di Paolo , M. Morissette , M.E. Tremblay , A. Parent , M. Parent

{"title":"Serotonin innervation of the subthalamic nucleus in parkinsonian monkeys","authors":"C.V.L. Delmas , J. Munro , M. Bérard , T. Di Paolo , M. Morissette , M.E. Tremblay , A. Parent , M. Parent","doi":"10.1016/j.nbd.2025.106938","DOIUrl":"10.1016/j.nbd.2025.106938","url":null,"abstract":"<div><div>The subthalamic nucleus (STN), the main driving force of the basal ganglia, is innervated by brainstem serotonin (5-HT) neurons with highly plastic axonal arborization. A pathologically-induced rearrangement of the ascending 5-HT projections could contribute to the disrupted firing pattern of STN neurons observed in Parkinson's disease (PD). This light and electron microscope study was designed to characterize the neuroadaptive changes of 5-HT inputs to the different functional territories of the STN in four cynomolgus monkeys (<em>Macaca fascicularis</em>) rendered parkinsonian by systemic injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and four control animals. Using an unbiased stereological approach, we report a significant decrease of the density of 5-HT axon varicosities immunolabeled for the 5-HT membrane transporter (SERT), across all STN functional territories of MPTP-treated monkeys. In MPTP-treated animals, the SERT+ axon varicosities are larger than in control monkeys. In both experimental conditions they are only partially synaptic. A preserved length of 5-HT axons in the STN along with a conserved number of 5-HT neurons in the dorsal raphe nucleus is observed. Overall, our results indicate that, in parkinsonian monkeys, the 5-HT axons projecting to the STN are preserved but endowed with significantly less axon varicosities. Such neuroadaptive change could lead to a lower ambient level of 5-HT in this basal ganglia component, representing a compensatory mechanism designed to cope with the hyperexcitability of STN neurons that is known to occur in PD.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"211 ","pages":"Article 106938"},"PeriodicalIF":5.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143921875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Brain proteome changes after intracerebral hemorrhage in aged male and female mice 老年雌雄小鼠脑出血后脑蛋白质组的变化。

IF 5.1 2区医学

Neurobiology of Disease Pub Date : 2025-05-02 DOI: 10.1016/j.nbd.2025.106936

Sivaraman Kuppuswamy, Noah J. Watson, William Luke Ledford, Blake A. Pavri, Wenbo Zhi, Mary Gbadebo, Frederick Bonsack, Hongyan Xu, Sangeetha Sukumari-Ramesh

{"title":"Brain proteome changes after intracerebral hemorrhage in aged male and female mice","authors":"Sivaraman Kuppuswamy, Noah J. Watson, William Luke Ledford, Blake A. Pavri, Wenbo Zhi, Mary Gbadebo, Frederick Bonsack, Hongyan Xu, Sangeetha Sukumari-Ramesh","doi":"10.1016/j.nbd.2025.106936","DOIUrl":"10.1016/j.nbd.2025.106936","url":null,"abstract":"<div><div>Aging is an independent predictor of adverse outcomes after intracerebral hemorrhage (ICH), a stroke subtype with no effective treatment. Despite the expected increase in the incidence of ICH due to population aging and the widespread use of anticoagulants, preclinical studies with aged animal subjects are lacking, and the pathophysiology of ICH in aged subjects has yet to be defined. Herein, we attempt to characterize the brain proteomic changes after ICH using an unbiased label- free quantitative proteomics approach and bioinformatics. To this end, aged male and female mice (18–24 months old) were subjected to sham/ICH. Mice were euthanized on day 3 post-surgery, and ipsilateral brain tissue was collected and subjected to LC-MS/MS analysis. Considering sex as a biological variable, the data derived from males and females were separately analyzed. The proteomics analysis revealed 133 differentially expressed proteins (DEPs) between the sham and ICH groups in male subjects. Among the DEPs, 98 proteins were downregulated, and 35 proteins were upregulated after ICH, compared to sham. In aged female mice, 315 DEPs were identified, of which 221 proteins were downregulated, and 94 proteins were upregulated after ICH compared to sham. The mass spectrometry data was validated using immunohistochemistry or western blot analysis, and the bioinformatics analysis revealed a comprehensive understanding of the signaling pathways associated with ICH. Some DEPs in both aged male and female mice that could play roles in ICH pathology were 14–3-3 proteins and S100-A9. The study also revealed that mitochondrial dysfunction could be a critical regulator of ICH-induced acute brain damage. Overall, the generated proteomics data could help develop hypothesis-driven functional analysis and delineate the complex pathobiology of ICH.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"212 ","pages":"Article 106936"},"PeriodicalIF":5.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Intermittent fasting produces antidepressant-like effects by modulating dopamine D1 receptors in the medial prefrontal cortex 间歇性禁食通过调节内侧前额皮质的多巴胺D1受体产生类似抗抑郁的效果

IF 5.1 2区医学

Neurobiology of Disease Pub Date : 2025-04-29 DOI: 10.1016/j.nbd.2025.106931

Jingjing Piao , Hongyu Chen , Xinmiao Piao , Ziqian Cheng , Fangyi Zhao , Ranji Cui , Bingjin Li

{"title":"Intermittent fasting produces antidepressant-like effects by modulating dopamine D1 receptors in the medial prefrontal cortex","authors":"Jingjing Piao , Hongyu Chen , Xinmiao Piao , Ziqian Cheng , Fangyi Zhao , Ranji Cui , Bingjin Li","doi":"10.1016/j.nbd.2025.106931","DOIUrl":"10.1016/j.nbd.2025.106931","url":null,"abstract":"<div><div>Nutritional psychiatry has gained increasing attention, particularly in exploring dietary interventions for depression treatment. As a potential non-drug intervention, intermittent fasting (IF) has gradually attracted the interest of researchers, but its specific neurobiological mechanisms in depression remain unclear. The medial prefrontal cortex (mPFC) dopamine D1 receptors (Drd1) are significant in stress response and serve as a molecular target for rapid-acting antidepressants. Our previous study indicated that 9-h fasting produces an antidepressant-like effect by modulating dopamine (DA) receptors. However, whether IF produces antidepressant-like effects through actions on DA receptor-mediated mechanisms remains unclear. Here, we investigated the effects of IF on improving depression-like behavior induced by Chronic Unpredictable Mild Stress (CUMS) in mice and explored whether these effects are regulated by Drd1. We found that IF alleviated CUMS-induced depression-like behavior, increased c-Fos expression in the mPFC and hippocampus of CUMS mice, and activated the Drd1-cAMP-PKA-DARPP-32-CREB-BDNF signaling pathway. The antidepressant-like effects of IF were reversed by the Drd1 antagonist SCH23390. Additionally, optogenetic activation of Drd1-expressing neurons in the mPFC improved CUMS-induced depression-like behavior, while optogenetic inhibition suppressed the IF-induced antidepressant-like effects. These findings imply that Drd1 plays a crucial role in the antidepressant-like effects of IF and offer valuable insights into the potential application of IF in clinical depression treatment.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"211 ","pages":"Article 106931"},"PeriodicalIF":5.1,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143899801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Proximity extension assay reveals serum inflammatory biomarkers in two amyotrophic lateral sclerosis cohorts 邻近扩展试验揭示了两个肌萎缩性侧索硬化队列的血清炎症生物标志物

IF 5.1 2区医学

Neurobiology of Disease Pub Date : 2025-04-28 DOI: 10.1016/j.nbd.2025.106933

Yujing Chen , Sujuan Sun , Ninglu Gao , Zetai Bai , Wenfei Yu , Bing Zhao , Yan Yun , Xiaohan Sun , Pengfei Lin , Wei Li , Yuying Zhao , Chuanzhu Yan , Shuangwu Liu

{"title":"Proximity extension assay reveals serum inflammatory biomarkers in two amyotrophic lateral sclerosis cohorts","authors":"Yujing Chen , Sujuan Sun , Ninglu Gao , Zetai Bai , Wenfei Yu , Bing Zhao , Yan Yun , Xiaohan Sun , Pengfei Lin , Wei Li , Yuying Zhao , Chuanzhu Yan , Shuangwu Liu","doi":"10.1016/j.nbd.2025.106933","DOIUrl":"10.1016/j.nbd.2025.106933","url":null,"abstract":"<div><div>Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease with both clinical and hereditary heterogeneity. Inflammation has been suggested to play an important role in ALS pathophysiology. In this study, we aimed to identify serum inflammatory alterations and develop effective inflammatory biomarkers to assist in the diagnosis of ALS. Through proximity extension assay (PEA), we investigated serum inflammatory alterations in two ALS cohorts compared with healthy controls (HCs), including sporadic ALS patients and genetic ALS patients. We found that CHIT1, OSM, SIRT2, CDCP1 and 5 other factors were significantly increased in sporadic ALS patients in both cohorts and that SIRT2, CDCP1 and 6 other factors were different between genetic ALS patients and HCs. Using XGBoost and binary logistic regression analysis, we developed a two-serum protein diagnostic panel (CHIT1 and CDCP1), and the area under the curve (AUC) was 0.904 in the original cohort and 0.907 in the replication cohort. Based on Mendelian Randomization (MR), OSM and SIRT2 are significantly associated with the risk of ALS. In conclusion, our study revealed a consistent and replicable serum inflammatory profile and developed a biomarker panel that can differentiate ALS patients from HCs in two cohorts, which may play an important role in advancing our current understanding of the inflammatory process and identifying novel therapeutic strategies for ALS patients.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"211 ","pages":"Article 106933"},"PeriodicalIF":5.1,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143903342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

The temporal onset of associations of cortical proteins with cognitive resilience vary during late life 皮层蛋白与认知弹性的关联的时间开始在晚年有所不同

IF 5.1 2区医学

Neurobiology of Disease Pub Date : 2025-04-28 DOI: 10.1016/j.nbd.2025.106927

Andrea R. Zammit , Tianhao Wang , Lei Yu , Shahram Oveisgharan , Vladislav A. Petyuk , Philip L. De Jager , Julie A. Schneider , David A. Bennett , Aron S. Buchman

{"title":"The temporal onset of associations of cortical proteins with cognitive resilience vary during late life","authors":"Andrea R. Zammit , Tianhao Wang , Lei Yu , Shahram Oveisgharan , Vladislav A. Petyuk , Philip L. De Jager , Julie A. Schneider , David A. Bennett , Aron S. Buchman","doi":"10.1016/j.nbd.2025.106927","DOIUrl":"10.1016/j.nbd.2025.106927","url":null,"abstract":"<div><h3>Background</h3><div>Cortical proteins associated with cognitive resilience have been identified but their temporal onset in older adults is unknown. We present a multistage approach to first identify cortical proteins associated with cognitive resilience and then examine their associated temporal onset.</div></div><div><h3>Methods</h3><div>We used data from a subset of 1088 decedents from two cohort-studies who had selected reaction monitoring proteomics from the dorsolateral prefrontal cortex, and at least 3 cognitive assessments. Cognition was assessed using a composite derived from 19 tests. We first used linear mixed-effects models to identify cortical proteins associated with cognitive resilience. We then used functional mixed-effects models to examine non-linear associations between proteins and cognitive resilience to identify their temporal onset.</div></div><div><h3>Results</h3><div>Mean age at death was 90 years (SD = 6.4); 69 % were female. On average, cognition started to decline at around 15 years before death, with accelerated decline in the last 7 years. We identified 40 proteins associated with cognitive resilience, of which 17 proteins also showed non-linear associations. Non-linear associations indicated that higher levels of 10 proteins were associated with slower cognitive decline between 23 and 4 years before death. In contrast, higher levels of 7 proteins were associated with faster decline only within the last 7 years before death.</div></div><div><h3>Conclusions</h3><div>Cognitive resilience proteins are differentially related to late-life cognitive aging; the onset of proteins that maintain cognition may begin many years before the onset of proteins that hasten cognitive decline. The temporal onset of cognitive resilience proteins may be crucial for timing efficacious interventions.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"211 ","pages":"Article 106927"},"PeriodicalIF":5.1,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143891108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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