Impact of APOE on cerebrovascular lipid profile in Alzheimer’s disease

载脂蛋白E对阿尔茨海默病脑血管脂质谱的影响

In this study, we conducted non-targeted lipidomics on cerebral vessels isolated from the middle temporal cortex of 89 postmortem human AD brains, representing varying degrees of CAA and different APOE genotypes: APOE ε2/ε3 (N = 9), APOE ε2/ε4 (N = 14), APOE ε3/ε3 (N = 21), APOE ε3/ε4 (N = 23), and APOE ε4/ε4 (N = 22). Taken together, our results suggest that cerebrovascular lipidomic profiles offer novel insights into the pathogenic mechanisms of AD, with specific lipid alterations potentially serving as biomarkers or therapeutic targets for AD.

在这项研究中，我们对从89例死后人类阿尔茨海默病（AD）患者大脑颞中回皮质分离出的脑血管进行了非靶向脂质组学分析，这些样本代表了不同程度的脑淀粉样血管病（CAA）和不同的载脂蛋白E（APOE）基因型：APOE ε2/ε3（N = 9）、APOE ε2/ε4（N = 14）、APOE ε3/ε3（N = 21）、APOE ε3/ε4（N = 23）和APOE ε4/ε4（N = 22）。综上所述，我们的研究结果表明，脑血管脂质组学特征为AD的致病机制提供了新的见解，特定的脂质改变有可能作为AD的生物标志物或治疗靶点。

REF: Inoue Y, Wang H, Heckman MG, et al. Impact of APOE on cerebrovascular lipid profile in Alzheimer's disease. Acta Neuropathol. 2025;150(1):39. Published 2025 Oct 8. doi:10.1007/s00401-025-02949-5 PMID: 41060400 PMCID: PMC12507989

Primary age-related tauopathy

原发性年龄相关性tau蛋白病

Primary age-related tauopathy (PART) was proposed in 2014 as a neuropathological term to describe patients with Alzheimer's-type medial temporal lobe neurofibrillary degeneration in the absence of significant β-amyloid pathology. Over the past decade, this designation has gained widespread adoption, helping to clarify the interpretation of biomarker profiles, delineate early-stage tauopathy in aging, and differentiate non-Alzheimer tauopathies from aging and classical Alzheimer disease. This review revisits PART ten years following its conception, critically evaluating its neuropathological features, clinical correlates, molecular underpinnings, and current limitations. We synthesize recent advances in neuroimaging, biomarkers, genetics, and epidemiology, explore the relationship between PART and other age-associated neurodegenerative processes, and propose revisions to the original PART criteria. While PART has served as a valuable framework for studying tau pathology in aging, key questions remain regarding its pathogenesis, clinical significance, and relationship to the broader spectrum of tauopathies. We highlight major gaps in knowledge and outline priorities for future research aimed at defining the mechanisms, biomarkers, and clinical criteria that will determine whether PART represents a distinct disease or a universal feature of human brain aging.

原发性年龄相关tau蛋白病（PART）于2014年作为一个神经病理学术语被提出，用于描述存在阿尔茨海默病型内侧颞叶神经原纤维变性但无明显β-淀粉样蛋白病变的患者。在过去十年中，这一名称得到了广泛采用，有助于明确生物标志物特征的解读，描绘衰老过程中早期tau蛋白病的特征，并将非阿尔茨海默病型tau蛋白病与衰老及典型阿尔茨海默病区分开来。本综述在PART概念提出十年后对其进行重新审视，严格评估其神经病理学特征、临床相关性、分子基础及当前存在的局限性。我们综合了神经影像学、生物标志物、遗传学和流行病学方面的最新进展，探讨了PART与其他年龄相关神经退行性病变过程之间的关系，并提议对最初的PART诊断标准进行修订。尽管PART为研究衰老过程中的tau蛋白病变提供了有价值的框架，但关于其发病机制、临床意义以及与更广泛的tau蛋白病谱系的关系等关键问题仍有待解答。我们强调了知识方面的主要空白，并列出了未来研究的重点，旨在明确相关机制、生物标志物和临床标准，以确定PART是一种独特的疾病，还是人类大脑衰老的普遍特征。

REF: Richardson TE, Walker JM, Farrell K, Oliveira TG, White CL 3rd, Crary JF. Primary age-related tauopathy. Acta Neuropathol. 2025;150(1):40. Published 2025 Oct 9. doi:10.1007/s00401-025-02943-x PMID: 41065841 PMCID: PMC12511220

Tumor-associated macrophages in meningiomas: a novel biomarker for poor survival outperforming the benefits of T cells

脑膜瘤中的肿瘤相关巨噬细胞：一种优于T细胞益处的不良生存新生物标志物

Tumor-associated macrophages (TAMs) represent the main immune cell population in various brain malignancies, but there is rare knowledge on the functional and, in particular, the prognostic role of TAMs in the meningioma (MGM) microenvironment. Here, we investigated TAM frequencies, activation state, survival-associated changes, and their association with tumor-infiltrating T lymphocytes (TILs) in two independent study samples comprising altogether 680 MGMs. Altogether, higher numbers of TAMs appear to be a hallmark of clinically aggressive behavior in newly diagnosed and recurrent MGMs. Unlike TILs, immunosuppressive TAMs seem to play a dominant role in the immunological landscape of MGMs with a significant negative impact on patient outcome, highlighting pro-tumoral TAMs to be an attractive treatment target in MGMs. Furthermore, our deconvolution approach presents a pipeline to computationally determine TAM and TIL infiltrates in the MGM microenvironment, which might be highly valuable for patient stratification for future immunotherapeutic treatments.

肿瘤相关巨噬细胞（TAMs）是各种脑恶性肿瘤中主要的免疫细胞群体，但对于TAMs在脑膜瘤（MGM）微环境中的功能，尤其是预后作用，我们所知甚少。在此，我们在两个独立的研究样本（共包含680例脑膜瘤）中研究了TAM的频率、激活状态、与生存相关的变化，以及它们与肿瘤浸润性T淋巴细胞（TILs）的关联。总体而言，在新诊断和复发性脑膜瘤中，TAM数量增多似乎是临床侵袭性行为的一个标志。与TILs不同，具有免疫抑制作用的TAMs似乎在脑膜瘤的免疫格局中起主导作用，对患者预后产生显著的负面影响，这凸显了促肿瘤性TAMs是脑膜瘤中一个有吸引力的治疗靶点。此外，我们的反卷积方法提供了一个在计算层面确定脑膜瘤微环境中TAM和TIL浸润情况的流程，这对于未来免疫治疗的患者分层可能具有极高的价值。

REF: Lotsch C, Warta R, Liu F, et al. Tumor-associated macrophages in meningiomas: a novel biomarker for poor survival outperforming the benefits of T cells. Acta Neuropathol. 2025;150(1):41. Published 2025 Oct 9. doi:10.1007/s00401-025-02948-6 PMID: 41065822 PMCID: PMC12511222

Molecular characterization and clinical features of diffuse midline glioma in the pediatric precision oncology registry INFORM

儿科精准肿瘤学登记系统INFORM中弥漫性中线胶质瘤的分子特征和临床特征

Diffuse midline glioma (DMG; a subtype of pediatric high-grade glioma) is a fatal disease in children, due to the localization in critical structures of the central nervous system, its invasive nature, and limited treatment options. Molecularly, DMG with loss of histone 3 K27 trimethylation (mostly through the typical K27M-mutation in histone 3) have been relatively well characterized, however, no unambiguous Achilles' heel for targeted therapeutic approaches could be identified to date. This study integrates detailed molecular characteristics of pediatric DMGs with clinical data in a large, international cohort in order to contribute to a better understanding necessary for further development of therapeutic approaches. This large, international, prospective DMG cohort combines comprehensive molecular characterization of the tumors with registry-level clinical data, thereby contributing to a better understanding of the underlying tumor biology, potential prognostic and predictive markers and the potential impact of targeted therapies.

弥漫性中线胶质瘤（DMG；儿童高级别胶质瘤的一种亚型）是儿童的致命性疾病，原因在于其位于中枢神经系统的关键结构，具有侵袭性，且治疗选择有限。从分子层面来看，组蛋白 3 赖氨酸 27 三甲基化缺失（主要是通过组蛋白 3 中典型的 K27M 突变）的 DMG 已得到相对较好的表征，但迄今为止，尚未确定靶向治疗方法的明确“致命弱点”。本研究将大型国际队列中儿童 DMG 的详细分子特征与临床数据相结合，以便为进一步开发治疗方法所需的更深入理解做出贡献。这个大型国际前瞻性 DMG 队列将肿瘤的全面分子特征与登记处级别的临床数据相结合，从而有助于更好地理解潜在的肿瘤生物学、潜在的预后和预测标志物以及靶向治疗的潜在影响。

REF: Pfaff E, Schramm K, Blattner-Johnson M, et al. Molecular characterization and clinical features of diffuse midline glioma in the pediatric precision oncology registry INFORM. Acta Neuropathol. 2025;150(1):42. Published 2025 Oct 11. doi:10.1007/s00401-025-02945-9 PMID: 41076459 PMCID: PMC12515216

Genetic and proteomic analysis identifies BAG3 as an amyloid-responsive regulator of neuronal proteostasis

基因和蛋白质组学分析确定BAG3为神经元蛋白质稳态的淀粉样蛋白响应调节因子

The autophagy-lysosome pathway (ALP) and the ubiquitin-proteasome system (UPS) are the primary protein degradative mechanisms maintaining proteostasis in neurons. However, the impact of human genetic variation on these pathways and the role of BAG3 are poorly understood, particularly in the context of Alzheimer's disease, where proteostatic dysfunction is a defining hallmark. We utilized a large panel of iPSCs from deeply phenotyped cohorts to interrogate genetic contributions to baseline autophagic flux and UPS activity in human neurons, and protein turnover was assessed using SILAC-based quantitative proteomics. Our findings identify BAG3 as a key modulator of proteostasis in human neurons. Its regulation across genetic backgrounds and pathological stimuli suggests a central role in maintaining degradation activities in Alzheimer's disease and related disorders.

自噬 - 溶酶体途径（ALP）和泛素 - 蛋白酶体系统（UPS）是维持神经元蛋白质稳态的主要蛋白质降解机制。然而，人类基因变异对这些途径的影响以及BAG3的作用尚不清楚，尤其是在蛋白质稳态功能障碍是典型特征的阿尔茨海默病背景下。我们利用来自深入表型分析队列的大量诱导多能干细胞（iPSCs），探究人类神经元中基因对基线自噬通量和UPS活性的贡献，并使用基于稳定同位素标记氨基酸细胞培养（SILAC）的定量蛋白质组学评估蛋白质周转。我们的研究结果表明，BAG3是人类神经元蛋白质稳态的关键调节因子。其在不同遗传背景和病理刺激下的调节作用表明，它在阿尔茨海默病及相关疾病中维持降解活性方面起着核心作用。

REF: Augur ZM, Fogo GM, Arbery MR, et al. Genetic and proteomic analysis identifies BAG3 as an amyloid-responsive regulator of neuronal proteostasis. Acta Neuropathol. 2025;150(1):43. Published 2025 Oct 14. doi:10.1007/s00401-025-02947-7 PMID: 41085772 PMCID: PMC12521299

LRRK2 kinase-mediated accumulation of lysosome-associated phospho-Rabs in tauopathies and synucleinopathies

在tau蛋白病和突触核蛋白病中，LRRK2激酶介导的溶酶体相关磷酸化Rabs蛋白的积累

Parkinson's disease (PD) pathogenic mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with endolysosomal dysfunction across cell types, and carriers of LRRK2 mutations variably present with phosphorylated tau and α-synuclein deposits in post-mortem analysis. LRRK2 mutations increase the phosphorylation of Rab substrates including Rab12 and Rab10. Rab12 and Rab10 are expressed in neuronal and non-neuronal cells with localization to membranes in the endolysosomal compartment, and lysosomal stress activates LRRK2 phosphorylation of Rabs. In this study, using antibodies directed to the LRRK2-mediated phosphorylation sites on Rab12 at amino acid Ser106 (pS106-Rab12) and Rab10 at amino acid Thr73 (pT73-Rab10), we test whether aberrant LRRK2 phosphorylation is associated with tau and/or α-synuclein pathology across clinically distinct neurodegenerative diseases. Finally, pT73-Rab10 is elevated and localizes to GVBs, but not tau and α-synuclein inclusions, in AD and LBD, including G2019S LRRK2 mutation carriers. These results implicate LRRK2 kinase activity and Rab phosphorylation in endolysosomal dysfunction in tau- and α-synuclein-associated neurodegenerative diseases.

富含亮氨酸重复序列激酶 2（LRRK2）的帕金森病（PD）致病突变与多种细胞类型的内溶酶体功能障碍有关，在尸检分析中，LRRK2 突变携带者会不同程度地出现磷酸化tau蛋白和α-突触核蛋白沉积。LRRK2 突变会增加包括 Rab12 和 Rab10 在内的 Rab 底物的磷酸化水平。Rab12 和 Rab10 在神经元和非神经元细胞中均有表达，定位于内溶酶体区室的膜上，溶酶体应激会激活 LRRK2 对 Rab 蛋白的磷酸化作用。在本研究中，我们使用针对 Rab12 第 106 位丝氨酸（pS106 - Rab12）和 Rab10 第 73 位苏氨酸（pT73 - Rab10）上 LRRK2 介导的磷酸化位点的抗体，来检测在不同临床类型的神经退行性疾病中，异常的 LRRK2 磷酸化是否与 tau 蛋白和/或α-突触核蛋白病变有关。最后，在阿尔茨海默病（AD）和路易体痴呆（LBD）患者（包括携带 G2019S LRRK2 突变的患者）中，pT73 - Rab10 水平升高并定位于颗粒空泡体（GVBs），但不定位在 tau 蛋白和α-突触核蛋白包涵体中。这些结果表明，LRRK2 激酶活性和 Rab 蛋白磷酸化与 tau 蛋白和α-突触核蛋白相关的神经退行性疾病中的内溶酶体功能障碍有关。

REF: Buck SA, Malankhanova T, Strader S, et al. LRRK2 kinase-mediated accumulation of lysosome-associated phospho-Rabs in tauopathies and synucleinopathies. Acta Neuropathol. 2025;150(1):44. Published 2025 Oct 23. doi:10.1007/s00401-025-02951-x PMID: 41128923 PMCID: PMC12549747

Brain-derived 5-hydroxymethylcytosine epigenetic scores are related to Alzheimer’s disease pathology and cognitive decline

脑源性 5-羟甲基胞嘧啶表观遗传评分与阿尔茨海默病病理和认知衰退相关

Cytosine modifications play critical roles in gene regulation and disease pathogenesis. Elucidating novel epigenetic contributions to Alzheimer's disease (AD) could advance diagnostic, prognostic, and therapeutic strategies. 5-hydroxymethylcytosine (5hmC), a stable and dynamic DNA modification, has emerging links to AD pathophysiology and potential uses as a biomarker. Cognitive decline, a hallmark of AD progression, varies across individuals and is not fully explained by classic pathological markers. Here, we aimed to develop and validate brain-derived 5hmC-based epigenetic scores to distinguish AD from non-AD pathology and examine their relationship to individual cognitive trajectories. This study extends prior work by translating brain 5hmC profiles into epigenetic scores that distinguish AD pathology and reflect individual cognitive trajectories. These findings highlight the potential of brain-derived 5hmC modifications as biomarkers for AD and as tools to advance research on disease progression, offering a new direction for epigenetics-informed clinical applications in AD.

胞嘧啶修饰在基因调控和疾病发病机制中起着关键作用。阐明阿尔茨海默病（AD）新的表观遗传学机制，有助于推动诊断、预后和治疗策略的发展。5-羟甲基胞嘧啶（5hmC）是一种稳定且动态的DNA修饰，与AD的病理生理学有着新的关联，并有作为生物标志物的潜在用途。认知衰退是AD进展的一个标志，在不同个体间存在差异，且经典病理标志物无法完全解释这种差异。在此，我们旨在开发并验证基于大脑来源5hmC的表观遗传评分，以区分AD与非AD病理，并研究其与个体认知轨迹的关系。本研究拓展了以往的工作，将大脑5hmC图谱转化为能区分AD病理并反映个体认知轨迹的表观遗传评分。这些发现凸显了大脑来源的5hmC修饰作为AD生物标志物的潜力，以及其作为推进疾病进展研究工具的价值，为AD的表观遗传学临床应用提供了新方向。

REF: Zhang Z, Capuano AW, Beadell A, et al. Brain-derived 5-hydroxymethylcytosine epigenetic scores are related to Alzheimer's disease pathology and cognitive decline. Acta Neuropathol. 2025;150(1):45. Published 2025 Oct 28. doi:10.1007/s00401-025-02950-y PMID: 41148349 PMCID: PMC12568897

Alpha-synuclein deposition patterns in Alzheimer’s disease: association with cortical amyloid beta and variable tau load

阿尔茨海默病中的α - 突触核蛋白沉积模式：与皮质β - 淀粉样蛋白及不同tau蛋白负荷的关联

Alpha-synuclein (α-syn) deposits are common in around half of the Alzheimer's disease (AD) cases. While direct and indirect protein interactions are suggested, the relationships between different protein aggregates remain poorly understood. Here, we aimed to characterize α-syn, amyloid beta (Aβ), and tau load distributions of AD patients. We show that next to age, sex, and ApoE genotype, the α-syn distribution in AD is related to different Aβ and tau loads. This may have therapeutic relevance for identifying patients who respond to Aβ immunotherapy related to tau burden and underpin the need to define α-syn pathology and distribution in early disease stages.

α-突触核蛋白（α-syn）沉积在约半数阿尔茨海默病（AD）病例中很常见。虽然有直接和间接的蛋白质相互作用的说法，但不同蛋白质聚集体之间的关系仍知之甚少。在此，我们旨在描述AD患者的α-突触核蛋白、β-淀粉样蛋白（Aβ）和tau蛋白的负荷分布情况。我们发现，除了年龄、性别和载脂蛋白E（ApoE）基因型外，AD患者体内的α-突触核蛋白分布与不同的Aβ和tau蛋白负荷有关。这可能在治疗上具有重要意义，有助于识别那些对与tau蛋白负担相关的Aβ免疫疗法有反应的患者，并强调了在疾病早期阶段明确α-突触核蛋白病理特征和分布情况的必要性。

REF: Neubauer A, Weissenbrunner D, Pekrun S, et al. Alpha-synuclein deposition patterns in Alzheimer's disease: association with cortical amyloid beta and variable tau load. Acta Neuropathol. 2025;150(1):46. Published 2025 Oct 30. doi:10.1007/s00401-025-02952-w PMID: 41165827 PMCID: PMC12575528