Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease

IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Acta Neuropathologica Pub Date : 2024-08-05 DOI:10.1007/s00401-024-02775-1
Nur Jury-Garfe, Javier Redding-Ochoa, Yanwen You, Pablo Martínez, Hande Karahan, Enrique Chimal-Juárez, Travis S. Johnson, Jie Zhang, Susan Resnick, Jungsu Kim, Juan C. Troncoso, Cristian A. Lasagna-Reeves
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Abstract

Asymptomatic Alzheimer’s disease (AsymAD) describes the status of individuals with preserved cognition but identifiable Alzheimer’s disease (AD) brain pathology (i.e., beta-amyloid (Aβ) deposits, neuritic plaques, and neurofibrillary tangles) at autopsy. In this study, we investigated the postmortem brains of a cohort of AsymAD subjects to gain insight into the mechanisms underlying resilience to AD pathology and cognitive decline. Our results showed that AsymAD cases exhibit enrichment in core plaques, decreased filamentous plaque accumulation, and increased plaque-surrounding microglia. Less pathological tau aggregation in dystrophic neurites was found in AsymAD brains than in AD brains, and tau seeding activity was comparable to that in healthy brains. We used spatial transcriptomics to characterize the plaque niche further and revealed autophagy, endocytosis, and phagocytosis as the pathways associated with the genes upregulated in the AsymAD plaque niche. Furthermore, the levels of ARP2 and CAP1, which are actin-based motility proteins that participate in the dynamics of actin filaments to allow cell motility, were increased in the microglia surrounding amyloid plaques in AsymAD cases. Our findings suggest that the amyloid-plaque microenvironment in AsymAD cases is characterized by the presence of microglia with highly efficient actin-based cell motility mechanisms and decreased tau seeding compared with that in AD brains. These two mechanisms can potentially protect against the toxic cascade initiated by Aβ, preserving brain health, and slowing AD pathology progression.

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淀粉样斑块微环境中小胶质细胞动态增强和 tau 种子减少有助于阿尔茨海默氏症患者的认知恢复能力。
无症状阿尔茨海默病(AsymAD)是指在尸检时认知能力得到保留,但大脑出现可识别的阿尔茨海默病(AD)病理变化(即β-淀粉样蛋白(Aβ)沉积、神经氨酸斑块和神经纤维缠结)的个体。在这项研究中,我们对一组AsymAD受试者的死后大脑进行了调查,以深入了解AD病理学和认知能力下降的恢复机制。我们的研究结果表明,AsymAD病例的核心斑块富集,丝状斑块堆积减少,斑块周围的小胶质细胞增多。与AD患者相比,AsymAD患者大脑中营养不良神经元的病理tau聚集较少,tau播种活性与健康大脑相当。我们利用空间转录组学进一步描述了斑块龛的特征,发现自噬、内吞和吞噬是与AsymAD斑块龛中基因上调相关的途径。此外,在AsymAD病例中,淀粉样蛋白斑块周围的小胶质细胞中ARP2和CAP1的水平升高,ARP2和CAP1是基于肌动蛋白的运动蛋白,参与肌动蛋白丝的动态变化以实现细胞运动。我们的研究结果表明,与AD病例相比,AsymAD病例中淀粉样蛋白斑块微环境的特点是存在具有高效肌动蛋白细胞运动机制的小胶质细胞,并且tau种子减少。这两种机制有可能抵御由Aβ引发的毒性级联,保护大脑健康,减缓AD病理进展。
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来源期刊
Acta Neuropathologica
Acta Neuropathologica 医学-病理学
CiteScore
23.70
自引率
3.90%
发文量
118
审稿时长
4-8 weeks
期刊介绍: Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.
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