Jury-Garfe Nur, You Yanwen, Martínez Pablo, Redding-Ochoa Javier, Karahan Hande, Johnson Travis S, Zhang Jie, Kim Jungsu, Troncoso Juan C, Lasagna-Reeves Cristian A
Stark Neuroscience Research Institute, Indiana University, Indianapolis, USA.
Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, USA.
bioRxiv. 2023 Jul 28:2023.07.27.550884. doi: 10.1101/2023.07.27.550884.
Asymptomatic Alzheimer's disease (AsymAD) describes the status of subjects with preserved cognition but with identifiable Alzheimer's disease (AD) brain pathology (i.e. Aβ-amyloid deposits, neuritic plaques, and neurofibrillary tangles) at autopsy. In this study, we investigated the postmortem brains of a cohort of AsymAD cases to gain insight into the underlying mechanisms of resilience to AD pathology and cognitive decline. Our results showed that AsymAD cases exhibit an enrichment of core plaques and decreased filamentous plaque accumulation, as well as an increase in microglia surrounding this last type. In AsymAD cases we found less pathological tau aggregation in dystrophic neurites compared to AD and tau seeding activity comparable to healthy control subjects. We used spatial transcriptomics to further characterize the plaque niche and found autophagy, endocytosis, and phagocytosis within the top upregulated pathways in the AsymAD plaque niche, but not in AD. Furthermore, we found ARP2, an actin-based motility protein crucial to initiate the formation of new actin filaments, increased within microglia in the proximity of amyloid plaques in AsymAD. Our findings support that the amyloid-plaque microenvironment in AsymAD cases is characterized by microglia with highly efficient actin-based cell motility mechanisms and decreased tau seeding compared to AD. These two mechanisms can potentially provide protection against the toxic cascade initiated by Aβ that preserves brain health and slows down the progression of AD pathology.
无症状阿尔茨海默病（AsymAD）描述的是认知功能未受损，但在尸检时具有可识别的阿尔茨海默病（AD）脑病理特征（即β-淀粉样蛋白沉积、神经炎性斑块和神经原纤维缠结）的受试者状态。在本研究中，我们调查了一组AsymAD病例的死后大脑，以深入了解对AD病理和认知衰退具有恢复力的潜在机制。我们的结果表明，AsymAD病例表现为核心斑块增多、丝状斑块积累减少，以及围绕后一种类型的小胶质细胞增多。与AD相比，我们发现AsymAD病例中营养不良性神经突中的病理性tau聚集较少，且tau播种活性与健康对照受试者相当。我们使用空间转录组学进一步表征斑块微环境，发现在AsymAD斑块微环境中，自噬、内吞作用和吞噬作用在上调最明显的通路中，但在AD中则不然。此外，我们发现ARP2（一种对启动新肌动蛋白丝形成至关重要的基于肌动蛋白的运动蛋白）在AsymAD淀粉样斑块附近的小胶质细胞内增加。我们的研究结果支持，与AD相比，AsymAD病例中的淀粉样斑块微环境的特征是具有高效基于肌动蛋白的细胞运动机制的小胶质细胞和tau播种减少。这两种机制可能提供保护，防止由β-淀粉样蛋白引发的毒性级联反应，从而保持大脑健康并减缓AD病理进程。
