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<p>Abnormal aggregation of amyloid-β protein (1–42) (Aβ<sub>42</sub>) is the primary pathology in Alzheimer’s disease (AD). Two types of Aβ<sub>42</sub> fibrils have been identified in the insoluble fraction of diseased human brains. Here, we report that the fraction previously deemed ‘soluble’ during sarkosyl extraction of AD brains actually harbors numerous amyloid fibrils, with a looser bundling than those in the insoluble fraction. Using cryo-electron microscopy (cryo-EM), we discover a third type (type III) of Aβ<sub>42</sub> fibril that is occasionally found in the soluble but not insoluble fraction of one AD brain. We also reveal that cryo-EM structures of Aβ<sub>42</sub> fibrils complexed with the positron emission tomography tracer AV-45 show a ligand-binding channel within type I but not type III Aβ<sub>42</sub> fibrils. In this binding channel, AV-45 engages with a vertical geometry. Through the discovery of this new structural polymorph of ex vivo Aβ<sub>42</sub> fibril, our study highlights the notable structural heterogeneity of Aβ fibrils among persons with AD.</p><p></p>

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Unraveling Alzheimer’s complexity with a distinct Aβ42 fibril type and specific AV-45 binding

  • 期刊论文

  • 发表日期：

    2025年6月10日

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  • Qinyue Zhao,
  • Youqi Tao,
  • Yuxuan Yao,
  • Kaien Liu,
  • Shiran Lv,
  • Bingyao Cui,
  • Weidi Xiao,
  • Tianyi Cao,
  • Weidong Li,
  • Feng Gao,
  • Yong Shen,
  • Chu Wang,
  • Chao Ma,
  • Wenying Qiu,
  • Cong Liu,
  • Dan Li

摘要

Abnormal aggregation of amyloid-β protein (1–42) (Aβ42) is the primary pathology in Alzheimer’s disease (AD). Two types of Aβ42 fibrils have been identified in the insoluble fraction of diseased human brains. Here, we report that the fraction previously deemed ‘soluble’ during sarkosyl extraction of AD brains actually harbors numerous amyloid fibrils, with a looser bundling than those in the insoluble fraction. Using cryo-electron microscopy (cryo-EM), we discover a third type (type III) of Aβ42 fibril that is occasionally found in the soluble but not insoluble fraction of one AD brain. We also reveal that cryo-EM structures of Aβ42 fibrils complexed with the positron emission tomography tracer AV-45 show a ligand-binding channel within type I but not type III Aβ42 fibrils. In this binding channel, AV-45 engages with a vertical geometry. Through the discovery of this new structural polymorph of ex vivo Aβ42 fibril, our study highlights the notable structural heterogeneity of Aβ fibrils among persons with AD.