Cognitive decline in community-dwelling older persons with primary age-related tauopathy: role of anatomical location of tangles and other co-existing brain pathologies

社区居住的原发性年龄相关性 tau 病变老年人群的认知衰退：缠结的解剖位置及其他共存脑部病变的作用

Primary age-related tauopathy (PART) has been associated with milder degrees of cognitive impairment, but the role of PART-related tangles, from the hippocampus, nearby inferior temporal neocortex, and the role of co-existing pathologies on cognitive decline are underappreciated. We used three harmonized community-based clinicopathologic studies to investigate the association of regional distributions of tangles and co-existing pathologies with cognitive decline. Overall, this study provides evidence that both extension of tangles to the nearby neocortex, specifically the inferior temporal, along with other co-pathologies, particularly LATE-NC, play a key role in cognitive decline in PART.

原发性年龄相关tau蛋白病（PART）与较轻程度的认知障碍有关，但海马、邻近的颞下新皮质中与PART相关的神经原纤维缠结的作用，以及共存病理状态对认知衰退的影响尚未得到充分认识。我们利用三项协调开展的基于社区的临床病理研究，来探究神经原纤维缠结的区域分布以及共存病理状态与认知衰退之间的关联。总体而言，本研究提供的证据表明，神经原纤维缠结延伸至邻近新皮质（特别是颞下新皮质），以及其他共存病理状态（尤其是晚发性Tau蛋白病神经病理改变，LATE - NC），在PART患者的认知衰退中起着关键作用。

REF: Agrawal S, Yu L, Barnes LL, Bennett DA, Boyle PA, Schneider JA. Cognitive decline in community-dwelling older persons with primary age-related tauopathy: role of anatomical location of tangles and other co-existing brain pathologies. Acta Neuropathol. 2025;150(1):8. Published 2025 Jul 24. doi:10.1007/s00401-025-02916-0 PMID: 40705123

Single-cell transcriptomic landscape of the neuroimmune compartment in amyotrophic lateral sclerosis brain and spinal cord

肌萎缩侧索硬化症脑和脊髓神经免疫区室的单细胞转录组图谱

Development of therapeutic approaches that target specific microglia responses in amyotrophic lateral sclerosis (ALS) is crucial due to the involvement of microglia in ALS progression. Our study identifies the predominant microglia subset in human ALS primary motor cortex and spinal cord as an undifferentiated phenotype with dysregulated respiratory electron transport. Moreover, we find that the interferon response microglia subset is enriched in donors with aggressive disease progression, while a previously described potentially protective microglia phenotype is depleted in ALS. Additionally, we observe an enrichment of non-microglial immune cell, mainly NK/T cells, in the ALS central nervous system, primarily in the spinal cord. These findings pave the way for the development of microglia subset-specific therapeutic interventions to slow or even stop ALS progression.

由于小胶质细胞参与肌萎缩侧索硬化症（ALS）的进展，因此开发针对ALS中特定小胶质细胞反应的治疗方法至关重要。我们的研究确定，人类ALS患者初级运动皮层和脊髓中的主要小胶质细胞亚群是一种呼吸电子传递失调的未分化表型。此外，我们发现干扰素反应性小胶质细胞亚群在疾病进展迅速的患者中更为丰富，而先前描述的具有潜在保护作用的小胶质细胞表型在ALS患者中缺失。此外，我们观察到非小胶质细胞免疫细胞（主要是NK/T细胞）在ALS患者的中枢神经系统中富集，主要富集于脊髓。这些发现为开发针对小胶质细胞亚群的治疗干预措施奠定了基础，有望减缓甚至阻止ALS的进展。

REF: Tuddenham JF, Fujita M, Lee E, et al. Single-cell transcriptomic landscape of the neuroimmune compartment in amyotrophic lateral sclerosis brain and spinal cord. Acta Neuropathol. 2025;150(1):10. Published 2025 Jul 29. doi:10.1007/s00401-025-02913-3 PMID: 40728732 PMCID: PMC12307561

Isomerized Aβ in the brain can distinguish the status of amyloidosis in the Alzheimer’s disease spectrum

大脑中的异构化β-淀粉样蛋白可区分阿尔茨海默病谱系中淀粉样病变的状态

Extracellular amyloid plaques, the pathognomonic hallmark of Alzheimer's disease (AD), are also observed in cognitively unimpaired subjects in the preclinical stages. Progressive accumulation of fibrillar amyloid-β (Aβ) as plaques and perivascular deposits occur two decades before clinical onset, making Aβ a long-lived peptide. To characterize the amyloid plaques biochemically, both the Aβ-load as well the post-translational modifications (PTMs) could serve as markers for distinguishing the pre-clinical stage compared to later prodromal and clinical stages of AD. Recently, we described the presence of extensive isomerization of the Aβ N-terminus in AD post-mortem brains that is significantly increased compared to the age-matched non-AD control brains with Aβ aggregates. In this report, we performed Lys-N enzymatic digestion followed by mass spectrometry-based quantitative analysis of the most common PTMs associated with plaque Aβ. Our results have implications for early therapeutic targeting of these modified species as well as potential for better biofluid biomarker development for drug efficacy monitoring.

细胞外淀粉样斑块是阿尔茨海默病（AD）的特征性标志，在临床前期认知功能未受损的受试者中也能观察到。纤维状β-淀粉样蛋白（Aβ）作为斑块和血管周围沉积物进行性积累的过程发生在临床发病前20年，这表明Aβ是一种长寿命肽。为了从生物化学角度对淀粉样斑块进行表征，Aβ负荷以及翻译后修饰（PTMs）都可以作为标志物，用于区分AD的临床前期与后续的前驱期和临床期。最近，我们发现AD患者尸检大脑中Aβ N端存在广泛的异构化现象，与有Aβ聚集物的年龄匹配的非AD对照大脑相比，这种异构化显著增加。在本报告中，我们进行了Lys - N酶切消化，随后对与斑块Aβ相关的最常见PTMs进行了基于质谱的定量分析。我们的研究结果对于早期针对这些修饰形式进行治疗干预具有指导意义，同时也为开发更好的生物流体生物标志物以监测药物疗效提供了可能。

REF: Mukherjee S, Coyle R, Dubois C, et al. Isomerized Aβ in the brain can distinguish the status of amyloidosis in the Alzheimer's disease spectrum. Acta Neuropathol. 2025;150(1):7. Published 2025 Jul 22. doi:10.1007/s00401-025-02914-2 PMID: 40696239

Amyloid-β plaque-associated microglia drive TSPO upregulation in Alzheimer’s disease

阿尔茨海默病中，淀粉样蛋白-β斑块相关小胶质细胞促使转运蛋白（TSPO）上调

Translocator protein 18 kDA (TSPO) imaging using positron emission tomography (PET) is widely used to assess neuroinflammation in Alzheimer's disease (AD). However, the significance of the increase in brain TSPO levels in AD pathophysiology is not known. Here, we show that in the 5XFAD transgenic mouse model, brain TSPO levels increase in an age-, brain region-, and sex-dependent fashion. In summary, TSPO is an early biomarker of neuroinflammation in the AD brain that first increases in the subiculum simultaneously with increased Aβ aggregation and serum Aβ1-42/Aβ1-40 ratio. The increased TSPO response in the 5XFAD mouse brain and in the brain from PSEN1-E280A mutation AD cases reflects Aβ-plaque-associated microglia with a high TSPO content. This microglia subtype is likely to promote the progression of AD pathology, neurodegeneration, and cognitive decline and their high TSPO content may serve as a target for TSPO ligand-based therapy.

利用正电子发射断层扫描（PET）进行的18kDA易位蛋白（TSPO）成像被广泛用于评估阿尔茨海默病（AD）中的神经炎症。然而，AD病理生理过程中大脑TSPO水平升高的意义尚不清楚。在这里，我们发现，在5XFAD转基因小鼠模型中，大脑TSPO水平以年龄、脑区和性别依赖的方式升高。总之，TSPO是AD大脑中神经炎症的早期生物标志物，其首先在下托区升高，同时伴有β-淀粉样蛋白（Aβ）聚集增加和血清Aβ1 - 42/Aβ1 - 40比值升高。5XFAD小鼠大脑以及携带PSEN1 - E280A突变的AD患者大脑中TSPO反应增强，反映了具有高TSPO含量的与Aβ斑块相关的小胶质细胞。这种小胶质细胞亚型可能会促进AD病理进展、神经变性和认知衰退，其高TSPO含量可能成为基于TSPO配体治疗的靶点。

REF: Martinez-Perez DA, McGlothan JL, Rodichkin AN, et al. Amyloid-β plaque-associated microglia drive TSPO upregulation in Alzheimer's disease. Acta Neuropathol. 2025;150(1):6. Published 2025 Jul 17. doi:10.1007/s00401-025-02912-4 PMID: 40676304 PMCID: PMC12271292

Loss of the lysosomal lipid flippase ATP10B leads to progressive dopaminergic neurodegeneration and parkinsonian motor deficits

溶酶体脂质翻转酶ATP10B缺失会导致进行性多巴胺能神经退行性变和帕金森病样运动障碍

ATP10B, a transmembrane lipid flippase located in late endosomes and lysosomes, facilitates the export of glucosylceramide and phosphatidylcholine by coupling this process to ATP hydrolysis. Recently, loss-of-function mutations in the ATP10B gene have been identified in Parkinson's disease patients, pointing to ATP10B as a candidate genetic risk factor. Previous studies have shown compromised lysosomal functionality upon ATP10B knockdown in human cell lines and primary cortical neurons. To investigate the role of ATP10B in Parkinson's disease neuropathology, specifically in the nigrostriatal dopaminergic system, we induced ATP10B knockdown specifically in substantia nigra pars compacta neurons of rats using viral vector technology. Additionally, midbrain neuronal cultures derived from ATP10B knock-out human induced pluripotent stem cells clones were used to study the impact of ATP10B loss in dopaminergic neurons in a more translational model. Taken together, our findings demonstrate that ATP10B depletion detrimentally impacts the viability of dopaminergic neurons both in vivo and in vitro. Moreover, a broader impact on the functionality of the nigrostriatal pathway was evidenced as rats with Atp10b knockdown exhibited motor impairments similar to those observed in Parkinson's disease patients.

ATP10B是一种位于晚期内体和溶酶体的跨膜脂质翻转酶，它通过将葡萄糖神经酰胺和磷脂酰胆碱的输出过程与ATP水解相偶联，促进这两种物质的输出。最近，在帕金森病患者中发现了ATP10B基因的功能丧失突变，这表明ATP10B是一个潜在的遗传风险因素。此前的研究显示，在人类细胞系和原代皮质神经元中敲低ATP10B会损害溶酶体功能。为了研究ATP10B在帕金森病神经病理学中的作用，特别是在黑质纹状体多巴胺能系统中的作用，我们利用病毒载体技术，在大鼠的黑质致密部神经元中特异性敲低ATP10B。此外，我们还使用了源自ATP10B敲除的人诱导多能干细胞克隆的中脑神经元培养物，在更具转化性的模型中研究ATP10B缺失对多巴胺能神经元的影响。综上所述，我们的研究结果表明，ATP10B缺失在体内和体外都会对多巴胺能神经元的存活能力产生不利影响。此外，有证据表明其对黑质纹状体通路的功能有更广泛的影响，因为敲低Atp10b的大鼠表现出与帕金森病患者相似的运动障碍。

REF: Sanchiz-Calvo M, Coccia E, Cawthorne C, et al. Loss of the lysosomal lipid flippase ATP10B leads to progressive dopaminergic neurodegeneration and parkinsonian motor deficits. Acta Neuropathol. 2025;150(1):5. Published 2025 Jul 17. doi:10.1007/s00401-025-02908-0 PMID: 40676227 PMCID: PMC12271281

Lipid mediated formation of antiparallel aggregates in cerebral amyloid angiopathy

脂质介导的脑淀粉样血管病中反平行聚集体的形成

Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder marked by amyloid-β (Aβ) deposition in blood vessel walls, leading to hemorrhage and recurring stroke. Despite significant overlap with Alzheimer's disease (AD) through shared Aβ pathology, the specific structural characteristics of Aβ aggregates in CAA and their variations between stages of disease severity are yet to be fully understood. Traditional approaches relying on brain-derived fibrils can potentially overlook the polymorphic heterogeneity and chemical associations within vascular amyloids. This study utilizes sub-diffraction, label-free optical photothermal infrared (O-PTIR) spectroscopic imaging to directly probe the chemical structure and heterogeneity of vascular amyloid aggregates within human brain tissues across different CAA stages. Our results demonstrate a clear increase in β-sheet content within vascular Aβ deposits corresponding to disease progression. Crucially, we identify a significant presence of antiparallel β-sheet structures, particularly prevalent in moderate/severe CAA. The abundance of antiparallel structures correlates strongly with co-localized lipids, implicating a lipid-mediated aggregation mechanism. We substantiate the ex-vivo observations using nanoscale AFM-IR spectroscopy and demonstrate that Aβ40 aggregated in-vitro with brain-derived lipids adopts antiparallel structural distributions mirroring those found in CAA vascular lesions. This work provides critical insights into the structural distributions of Aβ aggregates in CAA, highlighting the presence of polymorphs typically associated with transient intermediates, which may lead to alternate mechanisms for neurotoxicity.

脑淀粉样血管病（CAA）是一种脑血管疾病，其特征是淀粉样蛋白-β（Aβ）沉积在血管壁，导致出血和复发性中风。尽管通过共同的Aβ病理特征与阿尔茨海默病（AD）有显著重叠，但CAA中Aβ聚集体的具体结构特征及其在疾病严重程度不同阶段的变化仍有待充分了解。传统依赖脑源性原纤维的研究方法可能会忽略血管淀粉样蛋白内的多态异质性和化学关联。本研究利用亚衍射、无标记的光热红外（O - PTIR）光谱成像技术，直接探测不同CAA阶段人类脑组织中血管淀粉样聚集体的化学结构和异质性。我们的研究结果显示，随着疾病进展，血管Aβ沉积物中的β - 折叠含量明显增加。至关重要的是，我们发现反平行β - 折叠结构大量存在，尤其在中度/重度CAA中普遍存在。反平行结构的丰度与共定位的脂质密切相关，这暗示了一种脂质介导的聚集机制。我们使用纳米级原子力显微镜红外（AFM - IR）光谱技术证实了体外观察结果，并表明在体外与脑源性脂质聚集的Aβ40呈现出与CAA血管病变中相似的反平行结构分布。这项工作为CAA中Aβ聚集体的结构分布提供了关键见解，凸显了通常与瞬态中间体相关的多态体的存在，这可能会导致神经毒性的替代机制。

REF: de Oliveira AP, Baghel D, Holcombe B, et al. Lipid mediated formation of antiparallel aggregates in cerebral amyloid angiopathy. Acta Neuropathol. 2025;150(1):3. Published 2025 Jul 13. doi:10.1007/s00401-025-02911-5 PMID: 40652435 PMCID: PMC12256363