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Untangling the association of amyloid-β and tau with synaptic and axonal loss in Alzheimer's disease.

解开淀粉样蛋白-β 和tau蛋白与阿尔茨海默病突触和轴突丢失的关联。

  • 影响因子:7.52
  • DOI:10.1093/brain/awaa395
  • 作者列表:"Pereira JB","Janelidze S","Ossenkoppele R","Kvartsberg H","Brinkmalm A","Mattsson-Carlgren N","Stomrud E","Smith R","Zetterberg H","Blennow K","Hansson O
  • 发表时间:2021-02-12
Abstract

:It is currently unclear how amyloid-β and tau deposition are linked to changes in synaptic function and axonal structure over the course of Alzheimer's disease. Here, we assessed these relationships by measuring presynaptic (synaptosomal-associated protein 25, SNAP25; growth-associated protein 43, GAP43), postsynaptic (neurogranin, NRGN) and axonal (neurofilament light chain) markers in the CSF of individuals with varying levels of amyloid-β and tau pathology based on 18F-flutemetamol PET and 18F-flortaucipir PET. In addition, we explored the relationships between synaptic and axonal markers with cognition as well as functional and anatomical brain connectivity markers derived from resting-state functional MRI and diffusion tensor imaging. We found that the presynaptic and postsynaptic markers SNAP25, GAP43 and NRGN are elevated in early Alzheimer's disease i.e. in amyloid-β-positive individuals without evidence of tau pathology. These markers were associated with greater amyloid-β pathology, worse memory and functional changes in the default mode network. In contrast, neurofilament light chain was abnormal in later disease stages, i.e. in individuals with both amyloid-β and tau pathology, and correlated with more tau and worse global cognition. Altogether, these findings support the hypothesis that amyloid-β and tau might have differential downstream effects on synaptic and axonal function in a stage-dependent manner, with amyloid-related synaptic changes occurring first, followed by tau-related axonal degeneration.

摘要

: 目前尚不清楚淀粉样蛋白-β 和tau蛋白沉积如何与阿尔茨海默病病程中突触功能和轴突结构的变化相关。在这里,我们通过测量突触前 (突触体相关蛋白25,SNAP25; 生长相关蛋白43,GAP43),突触后 (神经颗粒蛋白,NRGN) 和轴突 (神经丝轻链) 来评估这些关系。基于18F-flutemetamol PET和18F-flortaucipir PET的具有不同水平的淀粉样蛋白-β 和tau病理学的个体的CSF中的标志物。此外,我们研究了关系突触和轴突标志物与认知以及功能和解剖大脑连通性标志物来源于静息态功能磁共振成像 (MRI) 和磁共振弥散张量成像.我们发现突触前和突触后标志物SNAP25、GAP43和NRGN在早期阿尔茨海默病即在没有tau病理学证据的淀粉样蛋白-β 阳性个体中。这些标志物与更大的淀粉样蛋白-β 病理学、更差的记忆和默认模式网络中的功能变化相关。相反,神经丝轻链在疾病后期是异常的,即在具有淀粉样蛋白-β 和tau病理的个体中,并且与更多的tau和更差的全局认知相关。总之,这些发现支持了这样的假设,即淀粉样蛋白-β 和tau蛋白可能以阶段依赖性方式对突触和轴突功能具有不同的下游影响,首先发生淀粉样蛋白相关的突触变化,然后是tau蛋白相关的轴突变性。

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