Pathogenic IgG from long COVID patients with neurological sequelae triggers sensitive but not cognitive impairments upon transfer into mice

来自有神经后遗症的长新冠患者的致病性IgG在转移到小鼠体内后会引发感觉障碍，但不会导致认知障碍。

Approximately 30% of long COVID patients still experience neurological symptoms (brain fog, pain, chronic fatigue) more than 4 months after the onset of COVID-19. This condition, known as 'neurological long COVID', remains poorly understood and might be explained by a persisting autoimmune response against nervous-derived self-antigens. The aim of this study is to determine whether IgG autoantibodies from long COVID patients with neurological sequelae can bind to central or peripheral nervous system epitopes and trigger neuropsychiatric symptoms upon passive transfer into mice, thereby mirroring patient-reported manifestations. These data demonstrate that IgGs from long COVID patients bind to peripheral sensory neurons and induce pain-related symptoms in mice. Our findings also support the hypothesis that autoantibodies mediate pain-related pathophysiology in the spectrum of long COVID symptoms.

大约30%的长新冠患者在感染新冠病毒4个多月后仍有神经症状（脑雾、疼痛、慢性疲劳）。这种被称为“神经型长新冠”的病症仍未被充分了解，可能是由针对神经源性自身抗原的持续自身免疫反应所致。本研究的目的是确定有神经后遗症的长新冠患者的IgG自身抗体是否能与中枢或外周神经系统表位结合，并在被动转移到小鼠体内后引发神经精神症状，从而重现患者所报告的症状表现。这些数据表明，长新冠患者的IgG抗体能与外周感觉神经元结合，并在小鼠体内诱发疼痛相关症状。我们的研究结果还支持了自身抗体介导长新冠症状谱中疼痛相关病理生理机制的假说。

REF: Mignolet M, Deroux C, Florkin T, et al. Pathogenic IgG from long COVID patients with neurological sequelae triggers sensitive but not cognitive impairments upon transfer into mice. Acta Neuropathol. 2026;151(1):50. Published 2026 Apr 29. doi:10.1007/s00401-026-03019-0 PMID: 42053865 PMCID: PMC13128780

The hypoxia-inflammation cycle as a key mechanism of smoldering inflammation and progression in multiple sclerosis

低氧 - 炎症循环作为多发性硬化症隐匿性炎症和病情进展的关键机制

Disease progression in multiple sclerosis (MS) remains a major unmet clinical challenge, as it is driven by pathogenic mechanisms that are poorly targeted by currently available disease-modifying treatments. Whereas acute focal inflammation characterizes the relapsing-remitting phase, converging neuropathological, imaging and experimental evidence identifies a chronic low-grade compartmentalized inflammatory process, the so-called "smoldering" inflammation, as a central driver of disease progression in MS. Recent findings suggest that both tissue hypoxia (primarily resulting from vascular dysfunction) and virtual hypoxia (a state of metabolic supply-demand mismatch culminating in bioenergetic failure) may critically contribute to the onset, persistence and compartmentalization of smoldering inflammation. In this review, we first delineate the pathological mechanisms underlying smoldering inflammation, distinguishing between lesional and extra-lesional features. We then examine the processes leading to tissue and virtual hypoxia in MS. As a key link between smoldering inflammation and hypoxia, we focused on the Hypoxia-Inducible Factor (HIF) signaling, the master regulator of cellular responses to hypoxia. Particularly, we reviewed recent evidence supporting its role as a central immunometabolic hub shaping immune and glial cell function within the hypoxic microenvironment of smoldering inflammation in MS. Finally, we critically evaluate the potential of the HIF signaling as a therapeutic target to hamper smoldering inflammation and disease progression in MS.

多发性硬化症（MS）的疾病进展仍然是一项重大且尚未得到满足的临床挑战，因为其致病机制无法被目前可用的疾病修饰疗法有效针对。急性局灶性炎症是复发 - 缓解期的特征，而神经病理学、影像学和实验证据均表明，一种慢性低度的局限性炎症过程，即所谓的“隐匿性”炎症，是MS疾病进展的核心驱动因素。近期研究结果表明，组织缺氧（主要由血管功能障碍引起）和虚拟缺氧（一种代谢供需不匹配最终导致生物能量衰竭的状态）可能对隐匿性炎症的发生、持续和局限性起到关键作用。在这篇综述中，我们首先阐述隐匿性炎症的病理机制，区分病灶内和病灶外的特征。然后，我们探讨MS中导致组织和虚拟缺氧的过程。作为隐匿性炎症与缺氧之间的关键联系，我们重点关注缺氧诱导因子（HIF）信号通路，它是细胞对缺氧反应的主要调节因子。特别是，我们回顾了近期支持其作为核心免疫代谢枢纽的证据，该枢纽塑造了MS隐匿性炎症缺氧微环境中免疫细胞和神经胶质细胞的功能。最后，我们严格评估了HIF信号通路作为治疗靶点以抑制MS隐匿性炎症和疾病进展的潜力。

REF: Missaglia M, Filippi M, Esposito F, Giordano A. The hypoxia-inflammation cycle as a key mechanism of smoldering inflammation and progression in multiple sclerosis. Acta Neuropathol. 2026;151(1):49. Published 2026 Apr 28. doi:10.1007/s00401-026-03021-6 PMID: 42047854

A severe neurodevelopmental syndrome linked to a South Asian founder variant in the UFMylation adaptor CDK5RAP3

与UFM化衔接蛋白CDK5RAP3中一个南亚奠基者变异相关的严重神经发育综合征

We investigated the pathogenicity of a homozygous intronic variant in CDK5RAP3, a key UFMylation adapter, in three individuals from two unrelated families with a lethal neurodevelopmental disorder. This study further highlights the therapeutic potential of ASO-based deep-intronic splicing defect correction.

我们对两个无亲缘关系家族中三名患有致命性神经发育障碍个体的关键泛素样修饰（UFMylation）衔接蛋白CDK5RAP3纯合内含子变异的致病性进行了研究。这项研究进一步凸显了基于反义寡核苷酸（ASO）的深度内含子剪接缺陷矫正的治疗潜力。

REF: Yuen M, Zhang K, Marchant RG, et al. A severe neurodevelopmental syndrome linked to a South Asian founder variant in the UFMylation adaptor CDK5RAP3. Acta Neuropathol. 2026;151(1):48. Published 2026 Apr 27. doi:10.1007/s00401-026-03017-2 PMID: 42045457 PMCID: PMC13121207

Loss of meningothelial identity and mesenchymal fate switching in NF2-mutant meningiomas

2型神经纤维瘤病（NF2）突变型脑膜瘤中脑膜上皮细胞特性丧失与间充质命运转变

Intracranial sarcomas can arise secondarily from primary brain tumors, including gliomas and meningiomas, either spontaneously or following radiotherapy. The current WHO classification recognizes sarcomatous transformation in several tumor entities; however, sarcomas arising from meningiomas remain poorly characterized and are regarded as a possible histological manifestation within the spectrum of anaplastic meningiomas. The results highlight limitations of morphology-based classification and emphasize the value of integrated molecular diagnostics in distinguishing these tumors from conventional high-grade meningiomas. Given their sarcoma-like behavior despite a meningioma ancestry, these tumors may not be adequately captured by current meningioma grading schemes.

颅内肉瘤可继发于原发性脑肿瘤，包括胶质瘤和脑膜瘤，自发发生或在放疗后出现。当前的世界卫生组织（WHO）分类认可几种肿瘤实体中存在肉瘤样转化；然而，起源于脑膜瘤的肉瘤仍缺乏充分的特征描述，被视为间变性脑膜瘤谱系内的一种可能的组织学表现。研究结果凸显了基于形态学分类的局限性，并强调了综合分子诊断在区分这些肿瘤与传统高级别脑膜瘤方面的价值。鉴于这些肿瘤尽管起源于脑膜瘤，但表现出肉瘤样行为，目前的脑膜瘤分级方案可能无法充分涵盖这些肿瘤。

REF: Rahmanzade R, Schweizer L, Schmid S, et al. Loss of meningothelial identity and mesenchymal fate switching in NF2-mutant meningiomas. Acta Neuropathol. 2026;151(1):46. Published 2026 Apr 25. doi:10.1007/s00401-026-03016-3 PMID: 42034799 PMCID: PMC13110230

Altered astrocyte–neuron crosstalk in progressive supranuclear palsy: integrated evidence from proteomics and magnetic resonance spectroscopy

进行性核上性麻痹中星形胶质细胞 - 神经元串扰的改变：来自蛋白质组学和磁共振波谱的综合证据

The anterior cingulate cortex (ACC), crucial for executive function, is frequently impaired in progressive supranuclear palsy (PSP), yet mechanisms underlying this selective vulnerability remain unclear. Given the integration of astrocytes into neural circuits, we hypothesized that astrocyte dysfunction and altered astrocyte-neuron crosstalk contribute to functional abnormalities in the ACC in PSP. To test this hypothesis, we conducted a multimodal analysis integrating SWATH-MS-based proteomics, histopathology, and in vivo magnetic resonance spectroscopy (MRS) in postmortem and living brains of patients with PSP and healthy controls (HCs). These findings demonstrate that multiple aspects of astrocyte-neuron crosstalk, including AQP4-mediated glymphatic clearance, energy metabolism, and neurotransmitter cycling, are altered in the ACC of patients with PSP. Such disruptions may contribute to neuronal dysfunction. Our study highlights astrocyte dysfunction as a central feature of the PSP pathophysiology.

前扣带回皮质（ACC）对执行功能至关重要，在进行性核上性麻痹（PSP）中常受损，但这种选择性易损性的潜在机制仍不清楚。鉴于星形胶质细胞参与神经回路，我们推测星形胶质细胞功能障碍和星形胶质细胞 - 神经元串扰改变导致了PSP患者ACC的功能异常。为验证这一假设，我们对PSP患者和健康对照（HCs）的尸检大脑和活体大脑进行了基于SWATH - MS的蛋白质组学、组织病理学和体内磁共振波谱（MRS）的多模态分析。这些发现表明，PSP患者ACC中星形胶质细胞 - 神经元串扰的多个方面，包括水通道蛋白4（AQP4）介导的类淋巴清除、能量代谢和神经递质循环，均发生了改变。这种破坏可能导致神经元功能障碍。我们的研究强调了星形胶质细胞功能障碍是PSP病理生理学的核心特征。

REF: Ono M, Kumagai Y, Hirata K, et al. Altered astrocyte-neuron crosstalk in progressive supranuclear palsy: integrated evidence from proteomics and magnetic resonance spectroscopy. Acta Neuropathol. 2026;151(1):45. Published 2026 Apr 24. doi:10.1007/s00401-026-03020-7 PMID: 42029746

Modification of early behavioural, physiological and neuropathological endpoints by syntaxin-6 knockout in a humanised P301S transgenic model of tauopathy

在人源化P301S转基因tau蛋白病模型中，Syntaxin - 6基因敲除对早期行为、生理和神经病理学终点的影响

Genetically mediated increased expression of syntaxin-6, a SNARE protein involved in intracellular protein trafficking, is a proposed risk mechanism for progressive supranuclear palsy and sporadic prion disease. Increased syntaxin-6 protein levels are also causally associated with Alzheimer's disease, suggesting it may have shared roles across multiple neurodegenerative diseases. However, no study has validated its functional role in tauopathies. To validate a role for syntaxin-6 in tauopathy pathogenesis, we knocked out syntaxin-6 in humanised P301S tauopathy mice. Taken together, this study functionally validates a role for syntaxin-6 in tauopathy pathogenesis, with syntaxin-6 knockout resulting in an early protective effect on multiple disease-relevant phenotypes in a humanised tauopathy model.

遗传介导的突触融合蛋白 6（一种参与细胞内蛋白质运输的 SNARE 蛋白）表达增加，被认为是进行性核上性麻痹和散发性朊蛋白病的一种风险机制。突触融合蛋白 6 蛋白水平升高也与阿尔茨海默病存在因果关联，这表明它可能在多种神经退行性疾病中发挥共同作用。然而，尚无研究证实其在tau 蛋白病中的功能作用。为了证实突触融合蛋白 6 在tau 蛋白病发病机制中的作用，我们在人源化 P301S tau 蛋白病小鼠中敲除了突触融合蛋白 6。综上所述，本研究从功能上证实了突触融合蛋白 6 在tau 蛋白病发病机制中的作用，在人源化tau 蛋白病模型中，敲除突触融合蛋白 6 对多种与疾病相关的表型具有早期保护作用。

REF: Hill E, Linehan J, Farmer M, et al. Modification of early behavioural, physiological and neuropathological endpoints by syntaxin-6 knockout in a humanised P301S transgenic model of tauopathy. Acta Neuropathol. 2026;151(1):44. Published 2026 Apr 22. doi:10.1007/s00401-026-03009-2 PMID: 42017988 PMCID: PMC13102793

Tau oligomerization induces nuclear lamina invagination and chromatin remodeling in Alzheimer’s disease

在阿尔茨海默病中，tau蛋白寡聚化诱导核纤层内陷和染色质重塑

The aggregation of the microtubule-associated protein tau into oligomeric complexes is strongly correlated with the onset and progression of neurodegeneration in Alzheimer's disease (AD). Increasing evidence implicates nuclear membrane disruption in AD and related tauopathies; however, whether this is a cause or consequence of neurodegeneration remains unresolved. Here, we show that nuclear lamina disruption emerges at the early Braak stages, coinciding with the initial formation of pathological tau aggregates in post-mortem AD brain tissue. This system revealed selective recruitment of oTau to the nuclear envelope and direct interactions with LBR and Lamin B2, leading to nuclear deformation and activation of the protein translational stress response. Together, these findings identify nuclear membrane disruption as an early and potentially causative event in tau-mediated neurodegeneration, establishing a mechanistic link between tau oligomerization, nuclear stress, and chromatin remodeling. Targeting nuclear destabilization may offer new therapeutic avenues for mitigating AD pathogenesis.

微管相关蛋白tau聚集成寡聚复合物与阿尔茨海默病（AD）神经退行性病变的发生和进展密切相关。越来越多的证据表明，核膜破坏与AD及相关tau蛋白病有关；然而，这是神经退行性病变的原因还是结果仍未明确。在这里，我们发现核纤层破坏出现在Braak早期阶段，与死后AD脑组织中病理性tau聚集体的初始形成同时发生。该体系揭示了寡聚tau（oTau）会选择性地募集到核膜，并与核纤层蛋白B受体（LBR）和核纤层蛋白B2直接相互作用，导致核变形并激活蛋白质翻译应激反应。总之，这些发现表明核膜破坏是tau介导的神经退行性病变中的一个早期且可能具有致病性的事件，在tau寡聚化、核应激和染色质重塑之间建立了机制联系。针对核不稳定状态进行干预可能为缓解AD发病机制提供新的治疗途径。

REF: Yuan S, Essepian N, Roberts R, et al. Tau oligomerization induces nuclear lamina invagination and chromatin remodeling in Alzheimer's disease. Acta Neuropathol. 2026;151(1):43. Published 2026 Apr 22. doi:10.1007/s00401-026-03018-1 PMID: 42017968 PMCID: PMC13102949

A model-based prion vaccine protects a transgenic mouse line carrying a Gerstmann–Sträussler–Scheinker disease mutation

一种基于模型的朊病毒疫苗可保护携带格斯特曼 - 施特劳斯勒 - 申克病突变的转基因小鼠品系

Prion diseases are transmissible, fatal, neurodegenerative disorders driven by the conformational misfolding of the cellular prion protein (PrPC) into an infectious, aggregation-prone conformer (PrPSc). While the accumulation of PrPSc represents the central pathogenic event, targeting it directly and specifically has proven difficult due to its structural heterogeneity and similarity to PrPC. Consequently, previous immunization efforts have largely focused on PrPC, though with limited success. Here, we employed a model-based approach to design a vaccine that specifically mimics immunogenic features hypothesized to be present on the surface of PrPSc. Our study demonstrates the feasibility of a model-based approach for prion vaccine design and targeting of the infectious prion protein, providing groundwork for future development of not only potential prion therapeutic interventions, but also targeting related neurodegenerative disorders characterized by protein misfolding.

朊病毒病是一种可传播的、致命的神经退行性疾病，由细胞型朊蛋白（PrPC）构象错误折叠成具有传染性、易于聚集的构象体（PrPSc）所引发。虽然PrPSc的积累是核心致病事件，但由于其结构的异质性以及与PrPC的相似性，直接且特异性地靶向它已被证明颇具难度。因此，此前的免疫接种工作主要集中在PrPC上，不过成效有限。在此，我们采用基于模型的方法来设计一种疫苗，该疫苗能特异性模拟假定存在于PrPSc表面的免疫原性特征。我们的研究证明了基于模型的方法用于朊病毒疫苗设计以及靶向传染性朊蛋白的可行性，不仅为未来潜在的朊病毒治疗干预措施的开发奠定了基础，也为靶向以蛋白质错误折叠为特征的相关神经退行性疾病提供了依据。

REF: Fang A, Tang X, Fleming M, et al. A model-based prion vaccine protects a transgenic mouse line carrying a Gerstmann-Sträussler-Scheinker disease mutation. Acta Neuropathol. 2026;151(1):41. Published 2026 Apr 17. doi:10.1007/s00401-026-03015-4 PMID: 41995880 PMCID: PMC13090231

Consensus statement on microglial and macrophage functions in gliomas

关于神经胶质瘤中小胶质细胞和巨噬细胞功能的共识声明

This international consensus statement synthesizes key findings on the complex roles of microglia and macrophages (tumor-associated microglia/macrophages or TAMs) in glioma progression and therapeutic resistance. Recent advances have highlighted the cellular, spatial, and temporal heterogeneity of TAMs, their functional plasticity, and the intricate interactions between TAMs, glioma stem cells, and the neuronal microenvironment, challenging the M1/M2 classification paradigm for TAMs in gliomas and other misconceptions. The statement emphasizes that glioma cells manipulate TAMs to suppress anti-tumor functions, while microglia-mediated modulation of neuron-glioma cell interactions promotes tumor progression. Furthermore, glioblastoma-derived extracellular vesicles (EVs) reprogram microglia to support tumor progression, offering novel therapeutic targets. To advance research and develop more effective treatments, the statement advocates for precision therapies targeting specific TAM subsets or functions, the use of bioengineered EVs as a therapeutic approach, and a shift away from simplistic terminology like "M1/M2" and "neuroinflammation". Ultimately, this new understanding can support innovative strategies to modulate the tumor microenvironment, turning immunosuppression into immunostimulation and improving outcomes for patients with glioblastoma and other types of gliomas.

这份国际共识声明综合了关于小胶质细胞和巨噬细胞（肿瘤相关小胶质细胞/巨噬细胞，即TAMs）在胶质瘤进展和治疗耐药中复杂作用的关键研究成果。近期进展凸显了TAMs在细胞、空间和时间上的异质性、其功能可塑性，以及TAMs、胶质瘤干细胞和神经元微环境之间的复杂相互作用，这对胶质瘤中TAMs的M1/M2分类范式及其他错误观念提出了挑战。声明强调，胶质瘤细胞会操纵TAMs以抑制抗肿瘤功能，而小胶质细胞介导的神经元 - 胶质瘤细胞相互作用的调节会促进肿瘤进展。此外，胶质母细胞瘤衍生的细胞外囊泡（EVs）会对小胶质细胞进行重编程以支持肿瘤进展，这为新的治疗靶点提供了可能。为推动研究并开发更有效的治疗方法，声明倡导针对特定TAM亚群或功能的精准治疗，将生物工程改造的EVs用作治疗手段，并摒弃“M1/M2”和“神经炎症”等过于简单化的术语。最终，这种新的认识有助于制定创新策略来调节肿瘤微环境，将免疫抑制转变为免疫刺激，改善胶质母细胞瘤和其他类型胶质瘤患者的预后。

REF: Zheng Y, Alzoubi I, Graeber MB, et al. Consensus statement on microglial and macrophage functions in gliomas. Acta Neuropathol. 2026;151(1):39. Published 2026 Apr 16. doi:10.1007/s00401-026-02999-3 PMID: 41991797 PMCID: PMC13086905