Neurobiology of Disease最新文献_第3页

Impedance-based phenotypic profiling of metabotropic glutamate receptor ligand responses in SCA1 human iPSC-derived neuronal cultures 在SCA1人类ipsc衍生的神经元培养中，基于阻抗的代谢性谷氨酸受体配体反应表型分析

IF 5.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2026-01-29 DOI: 10.1016/j.nbd.2026.107296

Laurie M.C. Kerkhof , Ronald A.M. Buijsen , Stefan Hartman , Barry A. Pepers , Linda M. van der Graaf , Jean-Philippe Frimat , Rongfang Liu , Laura H. Heitman , Willeke M.C. van Roon-Mom

Group 1 metabotropic glutamate receptors (mGluRs) are a family of G protein-coupled receptors (GPCRs) including mGluR1 and mGluR5. These receptors are expressed throughout the central nervous system and play an important role in synaptic plasticity. Dysfunction of mGluR1 in cerebellar Purkinje cells (PC) is observed in spinocerebellar ataxia type 1 (SCA1), an autosomal dominant neurodegenerative disorder caused by an expanded CAG repeat in the ATXN1 gene. MGluR1 dysfunction disrupts PC signaling and ultimately contributes to PC death and overall progressive cerebellar dysfunction observed in SCA1. To investigate mGluR1/5 pharmacology in the context of SCA1, mGluR1/5 function was assessed in SCA1 and control human induced pluripotent stem cell (hiPS)cell-derived neuronal cultures using impedance measurements in the xCELLigence real-time cell analyzer (RTCA) system. Culture conditions and protocols for evaluating glutamate receptor activity were first optimized. Subsequently, GRM1 and GRM5 expression levels were assessed and glutamatergic signaling function was characterized in SCA1 hiPS cell-derived neuronal cultures using both the non-selective endogenous ligand L-glutamate and the selective orthosteric agonist for mGluR1/5, (RS)-3,5-Dihydroxyphenylglycine. To specifically characterize mGluR1 function, mGluR1-specific positive- and negative allosteric modulators (Ro0711401 and JNJ16259685 respectively) were tested. Results showed reduced mGluR1 and decreased mGluR5 RNA expression levels and diminished mGluR1/5 responses in the SCA1 hiPS cell-derived neuronal cultures. These results underline the potential utility of impedance measurements for characterizing GPCR function and pharmacological testing in a high-throughput manner in patient-derived neuronal cultures.

1组代谢型谷氨酸受体（mGluRs）是一个G蛋白偶联受体（gpcr）家族，包括mGluR1和mGluR5。这些受体在整个中枢神经系统中表达，并在突触可塑性中发挥重要作用。脊髓小脑性共济失调1型（SCA1）是由ATXN1基因CAG重复扩增引起的常染色体显性神经退行性疾病，在脊髓小脑浦肯野细胞（PC）中观察到mGluR1功能障碍。MGluR1功能障碍破坏PC信号，最终导致PC死亡和SCA1观察到的整体进行性小脑功能障碍。为了研究mGluR1/5在SCA1背景下的药理学，我们在xCELLigence实时细胞分析仪（RTCA）系统中使用阻抗测量方法评估了mGluR1/5在SCA1和对照人诱导多能干细胞（hiPS）细胞来源的神经元培养中的功能。首先优化了谷氨酸受体活性测定的培养条件和方案。随后，使用非选择性内源性配体l-谷氨酸和mGluR1/5， (RS)-3,5-二羟基苯基甘氨酸的选择性正构激动剂，在SCA1 hiPS细胞来源的神经元培养中评估GRM1和GRM5的表达水平，并表征谷氨酸能信号传导功能。为了明确表征mGluR1的功能，我们测试了mGluR1特异性的阳性和阴性变构调节剂（分别为Ro0711401和JNJ16259685）。结果显示，在SCA1 hiPS细胞来源的神经元培养中，mGluR1和mGluR5 RNA表达水平降低，mGluR1/5反应减弱。这些结果强调了阻抗测量在表征GPCR功能和在患者来源的神经元培养中以高通量方式进行药理学测试的潜在效用。

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引用次数: 0

GDF-11, GDF-15, Jag-1, and leptin in neuronal-derived extracellular vesicles as aging-related biomarkers to identify individuals at risk of Alzheimer's dementia: A pilot study 神经元来源的细胞外囊泡中的GDF-11、GDF-15、jag1和瘦素作为识别阿尔茨海默氏痴呆风险个体的衰老相关生物标志物：一项初步研究

IF 5.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2026-01-28 DOI: 10.1016/j.nbd.2026.107291

Simona Lanzillotta , Virginia Boccardi , Barbara Zulli , Alessandro Napoli , Gabriele Paolozzi , Roberta Angelini , Barbara Ruzicka , Federica Fratini , Anna Giulia Guazzarini , Michela Scamosci , Patrizia Bastiani , Martina Alunno , Eric Westman , Fabio Di Domenico , Marzia Perluigi , Antonella Tramutola , Roberta Cecchetti , Tommaso Mazza , D. Allan Butterfield , Patrizia Mecocci , Eugenio Barone

Aging is the strongest risk factor for Alzheimer's disease (AD). Identifying reliable biomarkers of brain aging helps to predict functional decline and dementia onset. Evaluations of aging-related biomarkers in plasma and neuronal-derived extracellular vesicles (nEVs) from cognitively healthy and AD subjects, alongside post-mortem IPL brain samples from control (Ctr), pre-clinical AD (PCAD), mild cognitive impairment (MCI) and AD cases were performed. Cognitive tests, functional assessments, and MRI data were also included. Biomarkers in nEVs more accurately reflected brain pathology than those measured in plasma and showed stronger associations with cognitive and functional decline. Sex-specific patterns also emerged: GDF-15 was higher in nEVs from females with AD, whereas IL-6, IL-18 and Jag-1 were higher in nEVs from males with AD. A minimal nEV-derived panel including lower GDF-11 and higher GDF-15, Jag-1 and Leptin (after correction for age and sex) discriminated AD from Ctr and was associated with MRI-determined cortical atrophy in regions vulnerable to AD. These markers captured aging-related molecular trajectories that were disrupted in AD, and key associations observed in nEVs were confirmed in post-mortem brain tissue. Our results suggests that nEV-derived biomarkers capture early, brain-specific and sex-modulated aging signatures, providing superior sensitivity compared to plasma. Their convergence with post-mortem findings underscores their biological validity and translational potential. These results highlight the value of nEVs for stratifying individuals at higher risk of AD and support their integration into precision medicine approaches for dementia prevention.

衰老是阿尔茨海默病（AD）的最大危险因素。识别可靠的脑老化生物标志物有助于预测功能衰退和痴呆发病。对认知健康和AD受试者的血浆和神经元来源的细胞外囊泡（nev）中的衰老相关生物标志物进行了评估，同时对对照组（Ctr）、临床前AD （PCAD）、轻度认知障碍（MCI）和AD病例的死后IPL脑样本进行了评估。认知测试、功能评估和MRI数据也包括在内。新冠病毒中的生物标志物比血浆中的生物标志物更准确地反映了大脑病理，并显示出与认知和功能衰退的更强关联。性别特异性模式也出现了：女性AD患者的nev中GDF-15较高，而男性AD患者的nev中IL-6、IL-18和jag1较高。最小nev衍生的面板包括较低的GDF-11和较高的GDF-15， jag1和Leptin（在年龄和性别校正后）区分AD和Ctr，并与mri确定的AD易感区域皮质萎缩相关。这些标记捕获了AD中被破坏的与衰老相关的分子轨迹，而在nev中观察到的关键关联在死后脑组织中得到了证实。我们的研究结果表明，新能源汽车衍生的生物标志物捕获了早期、大脑特异性和性别调节的衰老特征，与血浆相比具有更高的灵敏度。它们与死后发现的一致性强调了它们的生物学有效性和转化潜力。这些结果突出了nev在对AD高风险个体进行分层方面的价值，并支持将其整合到预防痴呆症的精准医学方法中。

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引用次数: 0

Inhibition of the LHb glutamatergic pathway ameliorates depressive-like behaviors in a 6-hydroxydopamine-induced Parkinson's disease mouse model 抑制LHb谷氨酸能通路可改善6-羟多巴胺诱导的帕金森病小鼠模型中的抑郁样行为

IF 5.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2026-01-28 DOI: 10.1016/j.nbd.2026.107293

Juntao Cui, Di Zhao, Junchao Liu, Junliang Qian, Jun Wang, Limin Shi

Background

Depression is one of the most common non-motor disorders and neuropsychiatric comorbidities in Parkinson's disease (PD). The pathophysiology of depression in PD patients remains unclear and has been largely unexplored.

Method

In this study, we employed chemogenetics and pharmacology to modulate the lateral habenula (LHb) and its downstream brain regions, the rostromedial tegmental nucleus (RMTg) and the ventral tegmental area (VTA) in wild type (WT) and 6-hydroxydopamine (6-OHDA) mice, to investigate the potential mechanisms underlying the improvement of PD-related depression.

Results

Inhibition of LHb glutamatergic neurons, as well as disruption of the LHb-RMTg pathway, along with inhibition of RMTg GABAergic neurons ameliorates depressive-like behavior in 6-OHDA mice. Conversely, activation of LHb glutamatergic neurons, the LHb-RMTg pathway, and activation of RMTg GABAergic neurons exacerbated depressive-like behavior in WT and 6-OHDA mice. Notably, either inhibition or activation of the LHb-VTA pathway did not produce any significant changes in depressive-like behavior in WT and 6-OHDA mice. Additionally, activation of VTA DAergic neurons effectively ameliorating depressive-like behavior in 6-OHDA mice.

Conclusions

Inhibition of the LHb glutamatergic pathway ameliorates depressive-like behaviors in 6-OHDA PD mice model. These findings offer new insights for advancing research and developing novel treatments for PD-related depression.

抑郁症是帕金森病（PD）中最常见的非运动障碍和神经精神合并症之一。PD患者抑郁的病理生理机制尚不清楚，并且在很大程度上未被探索。方法采用化学遗传学和药理学方法，对野生型（WT）和6-羟多巴胺（6-OHDA）小鼠的外侧束（LHb）及其下游脑区、前内侧被盖核（RMTg）和腹侧被盖区（VTA）进行调控，探讨其改善pd相关性抑郁症的可能机制。结果LHb谷氨酸能神经元的抑制，以及LHb-RMTg通路的破坏，以及RMTg gaba能神经元的抑制，可改善6-OHDA小鼠的抑郁样行为。相反，LHb谷氨酸能神经元的激活、LHb-RMTg通路和RMTg gaba能神经元的激活会加重WT和6-OHDA小鼠的抑郁样行为。值得注意的是，无论是抑制还是激活LHb-VTA通路，都不会对WT和6-OHDA小鼠的抑郁样行为产生任何显著变化。此外，激活VTA能神经元可有效改善6-OHDA小鼠的抑郁样行为。结论抑制LHb谷氨酸能通路可改善6-OHDA PD小鼠抑郁样行为。这些发现为推进pd相关抑郁症的研究和开发新的治疗方法提供了新的见解。

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引用次数: 0

Associations between diseases of the mouth and mental disorders: A scoping review of longitudinal studies 口腔疾病与精神障碍之间的关系：纵向研究的范围综述

IF 5.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2026-01-26 DOI: 10.1016/j.nbd.2026.107285

Sudan Prasad Neupane , Ifeoma N. Onyeka , Vibeke H. Bull , Federico M. Daray

Background

Mental disorders and oral health conditions frequently co-occur. We mapped and critically reviewed the literature on longitudinal associations between oral health conditions and mental disorders.

Method

MEDLINE, Embase and PsycInfo were searched for longitudinal studies published during the last 25 years. Two reviewers independently screened, reviewed full-text and extracted data before synthesizing the evidence. Associations between oral and mental disorders were illustrated as Sankey diagrams. The review protocol was pre-registered (https://osf.io/vrpu9).

Findings

From 165 included studies, we identified 118 studies investigating 35 independent associations between 16 oral exposures and 12 mental disorder outcomes. Another 42 studies investigated 32 associations between 17 mental disorder exposures and 14 oral outcomes. Five studies reported bidirectional associations. Most reports linked tooth loss to Alzheimer's disease/other dementias (18 studies) and cognitive impairment (15 studies), with periodontitis linked to Alzheimer's disease/other dementias (16 studies). Conversely, depression (10 studies), dementia (6 studies) and sleep disorder (5 studies) were attributed to temporomandibular disorders (TMD; 10 studies), periodontitis (8 studies) and caries (7 studies) outcomes. Depressive and anxiety disorders were linked bidirectionally with TMD and eating disorders.

Interpretation

Prevention and early management of oral and mental disorders may mitigate their reciprocal risk, thereby lowering the overall disease burden.

精神障碍和口腔健康状况经常同时发生。我们绘制并批判性地回顾了口腔健康状况和精神障碍之间纵向关联的文献。方法检索medline、Embase和PsycInfo近25年发表的纵向研究。两位审稿人在综合证据之前独立筛选、审查全文并提取数据。口腔疾病和精神疾病之间的联系用桑基图来说明。审查方案已预先注册（https://osf.io/vrpu9）。从165个纳入的研究中，我们确定了118个研究，调查了16个口腔暴露与12个精神障碍结果之间的35个独立关联。另外42项研究调查了17种精神障碍暴露与14种口腔结果之间的32种关联。五项研究报告了双向关联。大多数报告将牙齿脱落与阿尔茨海默病/其他痴呆症（18项研究）和认知障碍（15项研究）联系起来，牙周炎与阿尔茨海默病/其他痴呆症（16项研究）有关。相反，抑郁症（10项研究）、痴呆（6项研究）和睡眠障碍（5项研究）被归因于颞下颌疾病（TMD； 10项研究）、牙周炎（8项研究）和龋齿（7项研究）的结果。抑郁症和焦虑症与TMD和饮食失调有双向关系。口腔和精神疾病的预防和早期管理可以减轻它们的相互风险，从而降低总体疾病负担。

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引用次数: 0

Tissue-specific immune and MAPK signatures in models of reduced Progranulin and Western diet 减少原蛋白和西方饮食模型的组织特异性免疫和MAPK特征

IF 5.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2026-01-26 DOI: 10.1016/j.nbd.2026.107287

Andrea R. Merchak , Maria Elizabeth de Sousa Rodrigues , Cassandra Cole , Noelle Neighbarger , Nilay Bhavsar , Rebecca L. Wallings , Valerie Joers , Jianjun Chang , Sean D. Kelly , Timothy R. Sampson , Malú Gámez Tansey

Neurodegenerative disorders such as frontotemporal dementia (FTD) have strong hereditary links, yet these genes do not have full penetrance and environmental influences determine the lifetime risk of disease development. Better understanding of the environmental risk factors that determine age of onset, progression, and severity is needed. How these risk factors interact with genetic predisposition for these disorders will allow clinicians to provide better lifestyle recommendations for people with a familial history and deliver more personalized medicine. Here we examine the dose-dependent effects of the gene encoding progranulin (Grn), one of the most common mutations associated with familial FTD. We utilize both homozygous loss and heterozygous knockdown of Grn with the objective of assessing how a western diet consisting of high-fat and high-carbohydrate intake modulates the inflammatory and metabolic hallmarks in middle-aged mice. We found that while full Grn loss leads to heighted antigen presentation machinery and immune cell infiltration in the brain after obesogenic diet, a heterozygous gene primarily affects the periphery. Yet, further examination by RNA sequencing reveals that heterozygous mice have a disruption of MAPK signaling in the brain highlighting early disruption in the neuronal landscape. Our findings are consistent with reports that in individuals with genetic predisposition for FTD due to a GRN mutation, a western-style diet exacerbates the cellular stress in the peripheral immune system and affects the function of the prefrontal cortex. These data further support the use of heterozygous Grn knockout mice as a model for prodromal FTD in addition to the more common Grn full knockout which may not as accurately reflect disease onset biology.

神经退行性疾病，如额颞叶痴呆（FTD）具有很强的遗传联系，但这些基因并不具有完全的外显率，环境影响决定了疾病发展的终生风险。需要更好地了解决定发病年龄、进展和严重程度的环境风险因素。这些风险因素如何与这些疾病的遗传易感性相互作用，将使临床医生为有家族病史的人提供更好的生活方式建议，并提供更个性化的药物。在这里，我们研究了编码前颗粒蛋白（Grn）的基因的剂量依赖性效应，这是与家族性FTD相关的最常见突变之一。我们利用纯合子缺失和杂合子敲低Grn，目的是评估由高脂肪和高碳水化合物摄入组成的西方饮食如何调节中年小鼠的炎症和代谢特征。我们发现，虽然在致肥性饮食后，Grn的完全缺失导致抗原呈递机制的增强和免疫细胞在大脑中的浸润，但杂合基因主要影响外周。然而，通过RNA测序的进一步研究表明，杂合小鼠的大脑中有MAPK信号的破坏，突出了神经元景观的早期破坏。我们的研究结果与一些报道一致，即在因GRN突变而具有FTD遗传易感性的个体中，西式饮食会加剧外周免疫系统中的细胞应激，并影响前额叶皮层的功能。这些数据进一步支持使用杂合Grn敲除小鼠作为前驱FTD的模型，而更常见的Grn完全敲除可能不能准确反映疾病发病生物学。

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引用次数: 0

The role of auxiliary GABAB receptor subunit KCTD16 in pain modulation 辅助GABAB受体亚基KCTD16在疼痛调节中的作用。

IF 5.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2026-01-25 DOI: 10.1016/j.nbd.2026.107286

Daniel Vasconcelos , Mario Heles , Pavel Adamek , Anirban Bhattacharyya , Adolf Melichar , Rostislav Turecek , Jiri Palecek

Chronic pain affects nearly 10% of the global population and remains a major clinical challenge due to the limited efficacy and adverse effects of current therapies. In this study, we identify the potassium channel tetramerization domain protein KCTD16 as a key modulator of GABA_B receptor mediated inhibition of nociceptive transmission. Immunohistochemical analysis revealed prominent KCTD16 expression in dorsal horn and dorsal root ganglion (DRG) neurons, consistent with a role in spinal nociceptive processing. KCTD16 knockout (KO) mice exhibited increased mechanical thresholds relative to wild-type (WT) littermates, while thermal sensitivity remained unchanged; this phenotype persisted following carrageenan-induced inflammation. The GABA_B receptor agonist Baclofen produced strong analgesic effects in WT mice under both basal and inflammatory conditions, whereas its anti-allodynic efficacy was significantly reduced in KO animals. Whole-cell patch-clamp recordings from dorsal horn neurons showed comparable baseline miniature excitatory and lower inhibitory postsynaptic currents (mEPSCs and mIPSCs) for KCTD16^−/−. However, following inflammation, Baclofen-induced suppression of excitatory transmission was potentiated in WT but markedly attenuated in KO neurons. Light-evoked synaptic inhibitory currents and calcium imaging of cultured DRG neurons further demonstrated enhanced Baclofen sensitivity in WT cells. These findings indicate that KCTD16 plays a critical role in presynaptic modulation of inhibitory control in the spinal dorsal horn, affecting the balance between the excitation and inhibition in nociceptive circuits. Collectively, these results demonstrate that KCTD16 modulates GABA_B receptor-dependent inhibitory control of nociceptive signaling and highlight the GABA_B receptor-KCTD16 complex as a promising new molecular target for effective pain treatments.

慢性疼痛影响着全球近10%的人口，由于目前治疗方法的疗效有限和不良反应，慢性疼痛仍然是一个重大的临床挑战。在这项研究中，我们发现钾通道四聚域蛋白KCTD16是GABAB受体介导的伤害性传递抑制的关键调节剂。免疫组织化学分析显示，KCTD16在背角和背根神经节（DRG）神经元中表达突出，与脊髓伤害感受加工的作用一致。KCTD16基因敲除（KO）小鼠相对于野生型（WT）小鼠表现出更高的机械阈值，而热敏性保持不变；这种表型在卡拉胶诱导的炎症后持续存在。GABAB受体激动剂巴氯芬在基础和炎症条件下对WT小鼠均有较强的镇痛作用，而在KO动物中其抗异动作用明显降低。来自背角神经元的全细胞膜片钳记录显示KCTD16-/-的基线微型兴奋性和低抑制性突触后电流（mEPSCs和mIPSCs）相当。然而，炎症发生后，巴氯芬诱导的兴奋传递抑制在WT中增强，而在KO神经元中明显减弱。培养DRG神经元的光诱发突触抑制电流和钙成像进一步显示WT细胞对巴氯芬的敏感性增强。这些结果表明，KCTD16在脊髓背角抑制控制的突触前调节中发挥了关键作用，影响了伤害回路中兴奋和抑制之间的平衡。总之，这些结果表明KCTD16调节GABAB受体依赖的伤害性信号的抑制控制，并突出了GABAB受体-KCTD16复合物作为有效治疗疼痛的有希望的新分子靶点。

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引用次数: 0

A Novel APP p.V742L variant in a patient with ischemic small vessel disease enhances FE65 signalling 缺血性小血管疾病患者的一种新的APP p.V742L变异增强了FE65信号

IF 5.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2026-01-25 DOI: 10.1016/j.nbd.2026.107280

Bas J.B. Voesenek , Julie W. Rutten , Monique P.C. Mulder , Hailiang Mei , Esther A.R. Nibbeling , Ellis S. van Etten , Willeke M.C. van Roon-Mom , Saskia A.J. Lesnik Oberstein , Elena Daoutsali , Ronald A.M. Buijsen

Pathogenic variants in the amyloid precursor protein gene (APP) have been linked to Alzheimer's disease and intracerebral haemorrhage resulting from cerebral amyloid angiopathy. In these disorders, variants are generally located within or surrounding the amyloid-beta domain of APP and mostly increase the production or aggregation properties of the toxic amyloid-beta peptide. Here, we report a novel APP p.V742L variant in the APP intracellular domain (AICD) in a patient with a clinical and neuroradiological ischemic small vessel disease phenotype and a positive family history. We investigate the functional consequences of the variant on AICD function.

We obtained patient fibroblasts through a skin biopsy and applied immunocytochemistry to examine the subcellular localization of APP. Subsequently, 3’ mRNA sequencing was deployed to investigate changes in gene expression. Finally, the effect of the variant on the binding of FE65 to AICD was investigated using co-immunoprecipitation followed by western blot.

Localization of APP p.V742L to lysosomes was increased, without affecting lysosomal motility. Transcriptome analysis showed altered expression of AICD target genes as well as dysregulation of genes relevant to the ischemic stroke phenotype. Finally, APP p.V742L was associated with an increased interaction with FE65, its most important intracellular binding partner.

Taken together, our data demonstrate that the APP p.V742L variant enhances the interaction of the AICD with FE65, resulting in dysregulation of gene transcription. This study illustrates the diverse roles of APP in brain disorders, and suggests ischemic small vessel disease as a novel APP-associated phenotype.

淀粉样蛋白前体蛋白基因（APP）的致病变异与阿尔茨海默病和脑淀粉样血管病引起的脑出血有关。在这些疾病中，变异通常位于APP的淀粉样蛋白- β结构域内或周围，并且大多增加了有毒淀粉样蛋白- β肽的产生或聚集特性。在这里，我们报告了APP胞内结构域（AICD）中一个新的APP p.V742L变异，该变异发生在一个具有临床和神经放射学缺血性小血管疾病表型和阳性家族史的患者身上。我们研究了该变异对AICD功能的功能后果。我们通过皮肤活检获得患者成纤维细胞，并应用免疫细胞化学检测APP的亚细胞定位。随后，我们利用3' mRNA测序来研究基因表达的变化。最后，采用免疫共沉淀法和western blot法研究该变异对FE65与AICD结合的影响。APP p.V742L在溶酶体上的定位增加，但不影响溶酶体的运动。转录组分析显示AICD靶基因表达改变以及与缺血性卒中表型相关的基因失调。最后，APP p.V742L与其最重要的胞内结合伙伴FE65的相互作用增加。综上所述，我们的数据表明，APP p.V742L变异增强了AICD与FE65的相互作用，导致基因转录失调。本研究阐明了APP在脑部疾病中的多种作用，并提示缺血性小血管疾病是一种新的APP相关表型。

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引用次数: 0

Pharmacological manipulation of nested oscillations in human iPSC-derived 2D neuronal networks. 人类ipsc衍生的2D神经元网络中嵌套振荡的药理操纵。

IF 5.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2026-01-24 DOI: 10.1016/j.nbd.2026.107281

Deborah Pré, Christian Cazares, Alexander T Wooten, Haowen Zhou, Isabel Onofre, Ashley Neil, Todd Logan, Ruilong Hu, Jan H Lui, Bradley Voytek, Anne G Bang

Dynamically coupled neural networks are fundamental to human cognition and behavior and are disrupted in neurodevelopmental disorders. The formation and dissolution of functional networks is thought to be driven by synchronized oscillatory bursts across large populations of neurons. The mechanisms driving the emergence of these rhythms, known as oscillogenesis, are not well understood, particularly in the human brain. Using multi-electrode arrays, we investigated oscillogenesis in human induced pluripotent stem cell 2D neural cultures at different developmental stages and under pharmacological challenges. We found that cultures exhibited nested oscillations that were reduced by GABAA receptor blockade and emerged earlier when the proportion of GABAergic neurons was increased. Pharmacological manipulations of voltage-gated potassium channels and cholinergic receptors modulated the pattern of nested oscillations. These results reveal the capacity of these 2D cultures to model oscillogenesis, and underscore the need for their continued refinement, paving the way for linking systems-level neural networks to human cognition and disease.

动态耦合神经网络是人类认知和行为的基础，在神经发育障碍中被破坏。功能网络的形成和分解被认为是由大量神经元的同步振荡爆发驱动的。驱动这些节律出现的机制，被称为示波器发生，还没有很好地理解，特别是在人脑中。使用多电极阵列，我们研究了不同发育阶段和药理挑战下人类诱导多能干细胞2D神经培养的示波器发生。我们发现，培养物表现出嵌套振荡，这种振荡因GABAA受体阻断而减少，当GABAA能神经元的比例增加时，这种振荡出现得更早。电压门控钾通道和胆碱能受体的药理学操作可调节巢状振荡的模式。这些结果揭示了这些2D培养物模拟示波器发生的能力，并强调了对其持续改进的需要，为将系统级神经网络与人类认知和疾病联系起来铺平了道路。

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引用次数: 0

Distinct Argonaute2-associated small RNA profiles in microglia and neurons drive cell-specific responses in a mouse model of temporal lobe epilepsy 在小鼠颞叶癫痫模型中，小胶质细胞和神经元中不同的argonaute2相关小RNA谱驱动细胞特异性反应

IF 5.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2026-01-22 DOI: 10.1016/j.nbd.2026.107284

Leticia Villalba-Benito , Justine Mathoux , Theresa Auer , Kaushik Narasimhan , Ruth Colbert , James P. Reynolds , Elizabeth Brindley , Aasia Batool , Thomas D.M. Hill , Mairead Diviney , Morten T. VenØ , Marco Prinz , Niamh M.C. Connolly , Dearbhaile Dooley , David C. Henshall , Gary P. Brennan

Small RNAs including microRNAs (miRNAs) and tRNA fragments (tRFs) are key post-transcriptional regulators of gene expression in temporal lobe epilepsy (TLE), but the cellular origin of these changes is often unclear. Here, we dissected the cell-type specific small RNA landscape, focussing on miRNA and tRFs, during epileptogenesis and in chronic epilepsy by profiling the RNA-induced silencing complex (RISC) using novel, transgenic mice with inducible expression of a FLAG-tagged Argonaute 2 protein driven specifically in neurons (Thy1-Ago2) or microglia (Cx3cr1-Ago2). We induced epilepsy in male mice via intra-amygdala microinjection of kainic acid and tracked miRNA expression over time in the hippocampus. Microglia and neurons displayed distinct and largely non-overlapping small RNA profiles across disease. Shortly following the epileptogenic insult, we detected a rapid microglial miRNA and tRF response which was sustained in chronic stages of the disease whereas small RNA changes in neurons displayed a delayed but sustained wave of unique changes as the disease progressed. Interestingly, our data reveals selective loading and incorporation of miRNAs into Ago2/RISC complexes, independent of overall abundance, in a cell- and disease-stage specific manner as well as differential processing of tRNAs in microglia compared to neurons. Additionally we found that certain epilepsy-associated miRNAs, previously considered ubiquitous, display dysregulation in multiple cell types while exhibiting cell-specific activity. Together our results demonstrate the cell-specific small RNA responses and functions to epileptogenic insults and shed further light on the complexity of post-transcriptional gene dysregulation in TLE. The findings indicate the potential advantages of targeted, cell-specific therapeutic strategies to effectively modulate miRNA pathways in epilepsy.

包括microRNAs （miRNAs）和tRNA片段（tRFs）在内的小rna是颞叶癫痫（TLE）基因表达的关键转录后调控因子，但这些变化的细胞起源往往不清楚。在这里，我们解剖了细胞类型特异性小RNA景观，重点关注miRNA和trf，在癫痫发生和慢性癫痫中，通过分析RNA诱导沉默复合物（RISC），使用新型转基因小鼠，诱导表达flag标记的Argonaute 2蛋白，特异性驱动神经元（Thy1-Ago2）或小胶质细胞（Cx3cr1-Ago2）。我们通过杏仁核内显微注射kainic酸诱导雄性小鼠癫痫，并随时间追踪海马miRNA的表达。小胶质细胞和神经元在不同疾病中表现出不同且基本上不重叠的小RNA谱。在癫痫性损伤发生后不久，我们检测到快速的小胶质细胞miRNA和tRF反应，这种反应在疾病的慢性阶段持续存在，而随着疾病的进展，神经元中的小RNA变化显示出延迟但持续的独特变化波。有趣的是，我们的数据揭示了mirna选择性加载和整合到Ago2/RISC复合物中，独立于总体丰度，以细胞和疾病阶段特异性的方式，以及与神经元相比，小胶质细胞中trna的差异加工。此外，我们发现某些癫痫相关的mirna，以前被认为是普遍存在的，在多种细胞类型中表现出失调，同时表现出细胞特异性活性。总之，我们的研究结果证明了细胞特异性小RNA对癫痫性损伤的反应和功能，并进一步阐明了TLE转录后基因失调的复杂性。这些发现表明，靶向性、细胞特异性治疗策略在有效调节癫痫miRNA通路方面具有潜在优势。

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引用次数: 0

The role of the kynurenine pathway in the pathophysiology of autism-like phenotype induced by maternal inflammation in male mice 犬尿氨酸通路在雄性小鼠母体炎症诱导的自闭症样表型病理生理中的作用。

IF 5.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2026-01-21 DOI: 10.1016/j.nbd.2026.107282

Danielle Santana-Coelho , Rafael dos Santos de Bessa , Rodrigo Neves Romcy-Pereira , Miguel A. de la Flor , Jason C. O'Connor

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with core symptoms that may include deficits in communication, social challenges, and repetitive/stereotyped behavior. The etiology of ASD is not well defined, but both genetic and environmental risk factors have been identified. In animal models, prenatal maternal immune activation precipitates the development of a behavioral phenotype resembling ASD, but the mechanisms by which this occurs are not fully understood. Inflammation can upregulate the kynurenine pathway metabolism through the enzyme indoleamine 2,3-dioxygenase-1 (IDO). Increased levels of kynurenines during development can have deleterious consequences leading to behavioral deficits in adulthood. We sought to determine whether the kynurenine pathway plays a pathogenic role in the development of an ASD-like phenotype using a well-characterized mouse model of maternal immune activation (MIA). Multiparous IDO null (IDO−/−) or C57BL/6 J wild-type dams were administered the viral mimetic polynosinic:polycytidylic acid (Poly IC) at gestational day 12.5. A similar immune response to Poly IC occurred in the maternal plasma and placenta of both genotypes, while kynurenine metabolism was only increased in the fetal tissue of WT mice exposed to Poly IC challenge. Interestingly, N-methyl-d-aspartate (NMDA) receptor subunit expression was reduced in the fetal brains of male WT, but not IDO−/−, after MIA with Poly IC. Here, we used machine-learning as an advanced method to evaluate ultrasonic vocalizations. Offspring exposed to prenatal MIA exhibited fewer and less complex ultrasonic vocalizations along with diminished social preference; however, MIA-induced repetitive/stereotyped behaviors were only present in WT mice. Taken together, our data indicate that fetal IDO1-dependent kynurenine metabolism mediates distinct components of the MIA-induced ASD-like phenotype in male mice, which may be related to alterations in the expression of NMDAR subunits during neurodevelopment.

自闭症谱系障碍（ASD）是一种神经发育障碍，其核心症状可能包括沟通缺陷、社交挑战和重复/刻板行为。ASD的病因尚不明确，但遗传和环境风险因素已被确定。在动物模型中，产前母体免疫激活促进了类似ASD的行为表型的发展，但其发生的机制尚不完全清楚。炎症可通过吲哚胺2,3-双加氧酶-1 （IDO）上调犬尿氨酸途径代谢。犬尿氨酸水平在发育过程中升高会导致成年后的行为缺陷。我们试图确定犬尿氨酸途径是否在asd样表型的发展中起致病作用，使用了一个具有良好特征的小鼠母体免疫激活（MIA）模型。在妊娠12.5天给多产IDO null （IDO-/-）或C57BL/6 J野生型母鼠注射病毒模拟多辛酸：多胞酸（Poly IC）。在两种基因型的母体血浆和胎盘中都出现了类似的对Poly IC的免疫应答，而暴露于Poly IC的WT小鼠的胎儿组织中犬尿氨酸代谢仅增加。有趣的是，在Poly IC MIA后，雄性WT胎儿大脑中的n -甲基-d-天冬氨酸（NMDA）受体亚基表达减少，但IDO-/-却没有。在这里，我们使用机器学习作为一种先进的方法来评估超声波发声。暴露于产前MIA的后代表现出越来越少的复杂超声发声，并且社会偏好降低；然而，mia诱导的重复/刻板行为仅存在于WT小鼠中。综上所述，我们的数据表明，胎儿ido1依赖性犬尿氨酸代谢介导了雄性小鼠mia诱导的asd样表型的不同组成部分，这可能与神经发育过程中NMDAR亚基表达的改变有关。

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引用次数: 0