A potential defense mechanism against amyloid deposition in cerebellum
A potential defense mechanism against amyloid deposition in cerebellum
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DOI：
10.1016/j.bbrc.2020.12.036
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发表时间：
2021-01-08
影响因子：
3.1
通讯作者：
Funamoto, Satoru
中科院分区：
文献类型：
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作者：
Shahnur, Alam;Nakano, Masaki;Funamoto, Satoru
β淀粉样蛋白（A β）是阿尔茨海默病（AD）脑中老年斑的主要成分。在AD患者中，老年斑通常在大脑皮层（CTX）而不是小脑（CBL）中观察到。然而，尚不清楚为什么CBL具有比CTX更少的A β沉积。因此，阐明CBL中A β沉积的抑制机制，不仅有助于了解AD的发病机制，而且有助于AD的防治。在这项研究中，我们探索了减少CBL中A β沉积的潜在机制。我们观察到CTX中A β水平的年龄依赖性升高高于人APP敲入AD模型小鼠的CBL，尽管我们在这些脑组织中未检测到间质液A β水平的显著差异。这些数据表明，CBL中较少的A β沉积是由于增强的A β清除而不是改变CBL中的A β产生。为了深入了解CBL中的A β清除，我们在脑组织中注射荧光标记的A β。重要的是，在注射后2小时内，CBL中荧光A β的扩散面积大约是CTX中的6倍。此外，CBL中注射的A β面积在24小时后急剧下降，并且CBL注射的A β在颈深淋巴结（DcLN）中被稳健地检测到。相反，CTX中荧光A β的扩散面积在72 h内是一致的，并且在DcLN中微弱地检测到CTX注射的A β。我们的数据表明，与脑膜淋巴系统相关的增强的A β引流是CBL中A β沉积减少的原因。(C)2020爱思唯尔公司All rights reserved.
Amyloid-beta (A beta) is the major component of senile plaques in Alzheimer's disease (AD) brains. Senile plaques are generally observed in cerebral cortex (CTX) rather than cerebellum (CBL) in AD patients. However, it is not clear why CBL has less A beta deposition than CTX. It is very important to elucidate the mechanism of suppressing A beta deposition in CBL, because it contributes to understanding of not only AD pathogenesis but also prevention and cure of AD. In this study, we explored to figure out the potential mechanism of reducing A beta deposition in CBL. We observed higher age-dependent elevation of A beta level in CTX rather than CBL of human APP knock-in AD model mice, although we detected no significant differences in the levels of interstitial fluid A beta in these brain tissues. These data imply that less A beta deposition in CBL is due to enhanced A beta clearance rather than altered A beta production in CBL. To gain insights into A beta clearance in CBL, we injected fluorescence-labeled A beta in brain tissues. Importantly diffusion area of fluorescent A beta in CBL was roughly six-times larger than that in CTX within 2 h of injection. In addition, injected A beta area in CBL decreased sharply after 24 h and CBL-injected A beta was robustly detected in deep cervical lymph nodes (DcLNs). In contrast, diffusion area of fluorescent A beta in CTX was consistent up to 72 h and CTX-injected A beta was faintly detected in DcLNs. Our data suggest that enhanced A beta drainage in association with meningeal lymphatic system is responsible for less A beta deposition in CBL. (C) 2020 Elsevier Inc. All rights reserved.