Neurobiology of Disease最新文献_第2页

Aberrant neuronal connectivity and network activity of neurons derived from patients with idiopathic schizophrenia 特发性精神分裂症患者神经元的异常连接和网络活动。

IF 5.1 2区医学

Neurobiology of Disease Pub Date : 2024-09-21 DOI: 10.1016/j.nbd.2024.106678

{"title":"Aberrant neuronal connectivity and network activity of neurons derived from patients with idiopathic schizophrenia","authors":"","doi":"10.1016/j.nbd.2024.106678","DOIUrl":"10.1016/j.nbd.2024.106678","url":null,"abstract":"<div><div>Schizophrenia (SCZ) is a psychiatric disorder with a strong genetic determinant. A major hypothesis to explain disease aetiology comprises synaptic dysfunction associated with excitatory-inhibitory imbalance of synaptic transmission, ultimately contributing to impaired network oscillation and cognitive deficits associated with the disease. Here, we studied the morphological and functional properties of a highly defined co-culture of GABAergic and glutamatergic neurons derived from induced pluripotent stem cells (iPSC) from patients with idiopathic SCZ. Our results indicate upregulation of synaptic genes and increased excitatory synapse formation on GABAergic neurons in co-cultures. In parallel, we observed decreased lengths of axon initial segments, concordant with data from <em>postmortem</em> brains from patients with SCZ. In line with increased synapse density, patch-clamp analyses revealed markedly increased spontaneous excitatory postsynaptic currents (EPSC) recorded from GABAergic SCZ neurons. Finally, MEA recordings from neuronal networks indicate increased strength of network activity, potentially in response to altered synaptic transmission and <em>E</em>-I balance in the co-cultures. In conclusion, our results suggest selective deregulation of neuronal activity in SCZ samples, providing evidence for altered synapse formation and synaptic transmission as a potential base for aberrant network synchronization.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142292079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Lateral thinking: Neurodegeneration of the cortical cholinergic system in Alzheimer's disease 横向思维阿尔茨海默病皮质胆碱能系统的神经变性。

IF 5.1 2区医学

Neurobiology of Disease Pub Date : 2024-09-21 DOI: 10.1016/j.nbd.2024.106677

{"title":"Lateral thinking: Neurodegeneration of the cortical cholinergic system in Alzheimer's disease","authors":"","doi":"10.1016/j.nbd.2024.106677","DOIUrl":"10.1016/j.nbd.2024.106677","url":null,"abstract":"<div><h3>Introduction</h3><div>Atrophy of the nucleus basalis of Meynert (NBM) is an early indicator of Alzheimer's disease (AD). However, reduced integrity of the NBM white matter tracts may be more relevant for cognitive impairment and progression to dementia than NBM volume. Research is needed to compare differences in NBM volume and integrity of the lateral and medial NBM tracts across early and later stages of AD progression.</div></div><div><h3>Methods</h3><div>187 participants were included in this study who were either healthy controls (HC; <em>n</em> = 50) or had early mild cognitive impairment (EMCI; n = 50), late MCI (LMCI; <em>n</em> = 37), or AD (n = 50). NBM volume was calculated using voxel-based morphometry and mean diffusivity (MD) of the lateral and medial NBM tracts were extracted using probabilistic tractography. Between group differences in NBM volume and tract MD were compared using linear mixed models controlling for age, sex, and either total intracranial volume or MD of a control mask, respectively. Associations between NBM volume and tract MD with executive function, memory, language, and visuospatial function were also analysed.</div></div><div><h3>Results</h3><div>NBM volume was smallest in AD followed by LMCI (<em>p</em> < 0.0001), with no difference between EMCI and HC. AD had highest MD for both tracts compared to all other groups (<em>p</em> < 0.01). Both MCI groups had higher lateral tract MD compared to HC (<em>p</em> < 0.05). Medial tract MD was higher in LMCI (<em>p</em> = 0.008), but not EMCI (<em>p</em> = 0.09) compared to HC. Higher lateral tract MD was associated with executive function (<em>p</em> = 0.001) and language (<em>p</em> = 0.02).</div></div><div><h3>Discussion</h3><div>Integrity of the lateral NBM tract is most sensitive to the earliest stages of AD and should be considered an important therapeutic target for early detection and intervention.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142292083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Expanded ATXN1 alters transcription and calcium signaling in SCA1 human motor neurons differentiated from induced pluripotent stem cells 扩增的 ATXN1 改变了从诱导多能干细胞分化而来的 SCA1 人类运动神经元的转录和钙信号转导。

IF 5.1 2区医学

Neurobiology of Disease Pub Date : 2024-09-20 DOI: 10.1016/j.nbd.2024.106673

{"title":"Expanded ATXN1 alters transcription and calcium signaling in SCA1 human motor neurons differentiated from induced pluripotent stem cells","authors":"","doi":"10.1016/j.nbd.2024.106673","DOIUrl":"10.1016/j.nbd.2024.106673","url":null,"abstract":"<div><div>Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited and lethal neurodegenerative disease caused by the abnormal expansion of CAG repeats in the <em>ATAXIN-1</em> (<em>ATXN1</em>) gene. Pathological studies identified dysfunction and loss of motor neurons (MNs) in the brain stem and spinal cord, which are thought to contribute to premature lethality by affecting the swallowing and breathing of SCA1 patients. However, the molecular and cellular mechanisms of MN pathogenesis remain unknown.</div><div>To study SCA1 pathogenesis in human MNs, we differentiated induced pluripotent stem cells (iPSCs) derived from SCA1 patients and their unaffected siblings into MNs. We examined proliferation of progenitor cells, neurite outgrowth, spontaneous and glutamate-induced calcium activity of SCA1 MNs to investigate cellular mechanisms of pathogenesis. RNA sequencing was then used to identify transcriptional alterations in iPSC-derived MN progenitors (pMNs) and MNs which could underlie functional changes in SCA1 MNs. We found significantly decreased spontaneous and evoked calcium activity and identified dysregulation of genes regulating calcium signaling in SCA1 MNs. These results indicate that expanded ATXN1 causes dysfunctional calcium signaling in human MNs.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142292082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 novel mouse model reproducing frontal alterations related to the prodromal stage of dementia with LEWY bodies 一种新型小鼠模型，再现了与前驱期LEWY体痴呆症相关的额叶改变。

IF 5.1 2区医学

Neurobiology of Disease Pub Date : 2024-09-20 DOI: 10.1016/j.nbd.2024.106676

{"title":"A novel mouse model reproducing frontal alterations related to the prodromal stage of dementia with LEWY bodies","authors":"","doi":"10.1016/j.nbd.2024.106676","DOIUrl":"10.1016/j.nbd.2024.106676","url":null,"abstract":"<div><h3>Background</h3><div>Dementia with Lewy bodies (DLB) is the second most common age-related neurocognitive pathology after Alzheimer's disease. Animal models characterizing this disease are lacking and their development would ameliorate both the understanding of neuropathological mechanisms underlying DLB as well as the efficacy of pre-clinical studies tackling this disease.</div></div><div><h3>Methods</h3><div>We performed extensive phenotypic characterization of a transgenic mouse model overexpressing, most prominently in the dorsal hippocampus (DH) and frontal cortex (FC), wild-type form of the human α-synuclein gene (mThy1-hSNCA, 12 to 14-month-old males). Moreover, we drew a comparison of our mouse model results to DH- and FC- dependent neuropsychological and neuropathological deficits observed in a cohort of patients including 34 healthy control subjects and 55 prodromal-DLB patients (males and females).</div></div><div><h3>Results</h3><div>Our study revealed an increase of pathological form of soluble α-synuclein, mainly in the FC and DH of the mThy1-hSNCA model. However, functional impairment as well as increase in transcripts of inflammatory markers and decrease in plasticity-relevant protein level were exclusive to the FC. Furthermore, we did not observe pathophysiological or Tyrosine Hydroxylase alterations in the striatum or substantia nigra, nor motor deficits in our model. Interestingly, the results stemming from the cohort of prodromal DLB patients also demonstrated functional deficits emanating from FC alterations, along with preservation of those usually related to DH dysfunctions.</div></div><div><h3>Conclusions</h3><div>This study demonstrates that pathophysiological impairment of the FC with concomitant DH preservation is observed at an early stage of DLB, and that the mThy1-hSNCA mouse model parallels some markers of this pathology.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142292078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Metabolic dysregulation in Huntington's disease: Neuronal and glial perspectives 亨廷顿氏病的代谢失调：神经元和神经胶质的视角。

IF 5.1 2区医学

Neurobiology of Disease Pub Date : 2024-09-19 DOI: 10.1016/j.nbd.2024.106672

{"title":"Metabolic dysregulation in Huntington's disease: Neuronal and glial perspectives","authors":"","doi":"10.1016/j.nbd.2024.106672","DOIUrl":"10.1016/j.nbd.2024.106672","url":null,"abstract":"<div><div>Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a mutant huntingtin protein with an abnormal CAG/polyQ expansion in the N-terminus of HTT exon 1. HD is characterized by progressive neurodegeneration and metabolic abnormalities, particularly in the brain, which accounts for approximately 20 % of the body's resting metabolic rate. Dysregulation of energy homeostasis in HD includes impaired glucose transporters, abnormal functions of glycolytic enzymes, changes in tricarboxylic acid (TCA) cycle activity and enzyme expression in the basal ganglia and cortical regions of both HD mouse models and HD patients. However, current understanding of brain cell behavior during energy dysregulation and its impact on neuron–glia crosstalk in HD remains limited. This review provides a comprehensive summary of the current understanding of the differences in glucose metabolism between neurons and glial cells in HD and how these differences contribute to disease development compared with normal conditions. We also discuss the potential impact of metabolic shifts on neuron–glia communication in HD. A deeper understanding of these metabolic alterations may reveal potential therapeutic targets for future drug development.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142292084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Alpha-synuclein modulates the repair of genomic DNA double-strand breaks in a DNA-PKcs-regulated manner α-突触核蛋白以DNA-PKcs调控的方式调节基因组DNA双链断裂的修复。

IF 5.1 2区医学

Neurobiology of Disease Pub Date : 2024-09-19 DOI: 10.1016/j.nbd.2024.106675

{"title":"Alpha-synuclein modulates the repair of genomic DNA double-strand breaks in a DNA-PKcs-regulated manner","authors":"","doi":"10.1016/j.nbd.2024.106675","DOIUrl":"10.1016/j.nbd.2024.106675","url":null,"abstract":"<div><div>α-synuclein (αSyn) is a presynaptic and nuclear protein that aggregates in important neurodegenerative diseases such as Parkinson's Disease (PD), Parkinson's Disease Dementia (PDD) and Lewy Body Dementia (LBD). Our past work suggests that nuclear αSyn may regulate forms of DNA double-strand break (DSB) repair in HAP1 cells after DNA damage induction with the chemotherapeutic agent bleomycin<sup>1</sup>. Here, we report that genetic deletion of αSyn specifically impairs the non-homologous end-joining (NHEJ) pathway of DSB repair using an extrachromosomal plasmid-based repair assay in HAP1 cells. Notably, induction of a single DSB at a precise genomic location using a CRISPR/Cas9 lentiviral approach also showed the importance of αSyn in regulating NHEJ in HAP1 cells and primary mouse cortical neuron cultures. This modulation of DSB repair is regulated by the activity of the DNA damage response signaling kinase DNA-PK<sub>cs</sub>, since the effect of αSyn loss-of-function is reversed by DNA-PK<sub>cs</sub> inhibition. Together, these findings suggest that αSyn plays an important physiologic role in regulating DSB repair in both a transformed cell line and in primary cortical neurons. Loss of this nuclear function may contribute to the neuronal genomic instability detected in PD, PDD and LBD and points to DNA-PK<sub>cs</sub> as a potential therapeutic target.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142292080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Astrocyte TrkB promotes brain injury and edema formation in ischemic stroke 星形胶质细胞 TrkB 促进缺血性中风的脑损伤和水肿形成。

IF 5.1 2区医学

Neurobiology of Disease Pub Date : 2024-09-18 DOI: 10.1016/j.nbd.2024.106670

{"title":"Astrocyte TrkB promotes brain injury and edema formation in ischemic stroke","authors":"","doi":"10.1016/j.nbd.2024.106670","DOIUrl":"10.1016/j.nbd.2024.106670","url":null,"abstract":"<div><div>Following ischemic stroke astrocytes undergo rapid molecular and functional changes that may accentuate tissue damage. In this study we identified the neurotrophin receptor TrkB in astrocytes as a key promoter of acute CNS injury in ischemic stroke. In fact, TrkB protein was strongly upregulated in astrocytes after human and experimental stroke, and transgenic mice lacking astrocyte TrkB displayed significantly smaller lesion volume, lower brain atrophy and better motor performance than control animals after transient middle cerebral artery occlusion. Neuropathological studies evidenced that edema directly correlated with astrogliosis and was limited in transgenic mice. Importantly, adaptive levels of the water channel AQP4 was astrocyte TrkB-dependent as AQP4 upregulation after stroke did not occur in mice lacking astrocyte TrkB. <em>In vitro</em> experiments with wild-type and/or TrkB-deficient astrocytes highlighted TrkB-dependent upregulation of AQP4 <em>via</em> activation of HIF1-alpha under hypoxia. Collectively, our observations indicate that TrkB signaling in astrocytes contributes to the development of edema and worsens cerebral ischemia.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0969996124002705/pdfft?md5=a3579dc67ed60f3eb452a11c17c6cf2c&pid=1-s2.0-S0969996124002705-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142292081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Prion protein pathology in Ubiquilin 2 models of ALS 优生素 2 ALS 模型中的朊病毒蛋白病理学

IF 5.1 2区医学

Neurobiology of Disease Pub Date : 2024-09-18 DOI: 10.1016/j.nbd.2024.106674

引用次数: 0

Multiscale spatio-temporal dynamics of UBE3A gene in brain physiology and neurodevelopmental disorders UBE3A 基因在脑生理学和神经发育障碍中的多尺度时空动态。

IF 5.1 2区医学

Neurobiology of Disease Pub Date : 2024-09-16 DOI: 10.1016/j.nbd.2024.106669

{"title":"Multiscale spatio-temporal dynamics of UBE3A gene in brain physiology and neurodevelopmental disorders","authors":"","doi":"10.1016/j.nbd.2024.106669","DOIUrl":"10.1016/j.nbd.2024.106669","url":null,"abstract":"<div><p>The <em>UBE3A</em> gene, located in the chromosomal region 15q11-13, is subject to neuron-specific genomic imprinting and it plays a critical role in brain development. Genetic defects of <em>UBE3A</em> cause severe neurodevelopmental disorders, namely the Angelman syndrome (AS) and the 15q11.2-q13.3 duplication syndrome (Dup15q). In the last two decades, the development of in vitro and in vivo models of AS and Dup15q were fundamental to improve the understanding of UBE3A function in the brain. However, the pathogenic mechanisms of these diseases remain elusive and effective treatments are lacking. Recent evidence suggests that UBE3A functions are both spatially and temporally specific, varying across subcellular compartments, brain regions, and neuronal circuits. In the present review, we summarize current knowledge on the role of UBE3A in neuronal pathophysiology under this spatio-temporal perspective. Additionally, we propose key research questions that will be instrumental to better understand the pathogenic mechanisms underpinning AS and Dup15q disorders and provide the rationale to develop novel therapies.</p></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0969996124002699/pdfft?md5=c4b43563bfbeb8def53afc9ec25efb10&pid=1-s2.0-S0969996124002699-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142254746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Dipeptidyl peptidase 4 deficiency improves survival after focal cerebral ischemia in mice and ameliorates microglia activation and specific inflammatory markers 二肽基肽酶 4 缺乏症可提高小鼠局灶性脑缺血后的存活率，并改善小胶质细胞活化和特定炎症标志物。

IF 5.1 2区医学

Neurobiology of Disease Pub Date : 2024-09-16 DOI: 10.1016/j.nbd.2024.106671

{"title":"Dipeptidyl peptidase 4 deficiency improves survival after focal cerebral ischemia in mice and ameliorates microglia activation and specific inflammatory markers","authors":"","doi":"10.1016/j.nbd.2024.106671","DOIUrl":"10.1016/j.nbd.2024.106671","url":null,"abstract":"<div><div>Dipeptidyl peptidase 4 (DPP4; CD26) is involved in the regulation of various metabolic, immunological, and neurobiological processes in healthy individuals. Observations based on epidemiological data indicate that DPP4 inhibition by gliptins, typically used in patients with diabetes, may reduce the risk for cerebral ischemia and may also improve related outcomes. However, as DPP4 inhibitor application is neither complete nor specific for suppression of DPP4 enzymatic activity and DPP4 has non-enzymatic functions as well, the variety of consequences is a matter of debate. Therefore, we here used DPP4 knock-out (KO) mice to analyze the specific contribution of DPP4 to cellular, immunological, and functional consequences of experimental focal cerebral ischemia.</div><div>We observed a significantly higher survival rate of DPP4 KO mice after ischemia, which was accompanied by a lower abundance of the pro-inflammatory chemokine CCL2 and reduced activation of Iba1-positive microglia cells in brain tissue of DPP4 KO mice. In addition, after ischemia for 24 h to 72 h, decreased concentrations of CCL5 and CCL12 in plasma and of CCL17 in brain tissue of DPP4 KO mice were observed when compared to wild type mice. Other aspects analyzed, such as the functional Menzies score, astrocyte activation and chemokine levels in plasma and brain tissue were affected by ischemia but appeared to be unaffected by the DPP4 KO genotype.</div><div>Taken together, experimental ablation of DPP4 functions in mice improves survival and ameliorates aspects of cellular and molecular inflammation after focal cerebral ischemia.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0969996124002717/pdfft?md5=c6796c8c16d17f0faec3440206e42d12&pid=1-s2.0-S0969996124002717-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142254699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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