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Updated: Jun 12, 2025
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Published on: April 23, 2010
Unraveling Alzheimer's complexity with a distinct Aβ42 fibril type and specific AV-45 binding
Qinyue Zhao1,2, Youqi Tao1,2, Yuxuan Yao1,2
1Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China.
Abstract:
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.
Insights
Alzheimer's disease research reveals a third type of amyloid-beta 42 (Aβ42) fibril in the soluble fraction of AD brains. This discovery highlights significant structural diversity in Aβ42 protein aggregates found in individuals with Alzheimer's disease.
Area of Science:
- Neuroscience
- Biochemistry
- Structural Biology
Background:
- Abnormal aggregation of amyloid-beta protein (1-42) (Aβ42) is a hallmark of Alzheimer's disease (AD).
- Previously, two main types of Aβ42 fibrils were identified in the insoluble fraction of AD brain tissue.
- The 'soluble' fraction was thought to contain fewer or no amyloid fibrils.
Purpose of the Study:
- To investigate the structural characteristics of Aβ42 aggregates in both soluble and insoluble fractions of AD brain tissue.
- To identify novel structural polymorphs of Aβ42 fibrils.
- To examine the interaction of Aβ42 fibrils with positron emission tomography (PET) tracers.
Main Methods:
- Sarkosyl extraction of AD brain tissue to separate soluble and insoluble fractions.
- Cryo-electron microscopy (cryo-EM) for high-resolution structural analysis of Aβ42 fibrils.
- Complexation of Aβ42 fibrils with the PET tracer AV-45 for structural investigation.
Main Results:
- Amyloid fibrils were identified in the previously 'soluble' fraction, exhibiting looser bundling compared to insoluble fibrils.
- A novel third type (type III) of Aβ42 fibril was discovered in the soluble fraction of one AD brain.
- Cryo-EM revealed a ligand-binding channel in type I Aβ42 fibrils, but not in type III, with AV-45 binding vertically within type I.
Conclusions:
- The study reveals significant structural heterogeneity of ex vivo Aβ42 fibrils in Alzheimer's disease.
- A third Aβ42 fibril polymorph (type III) exists and is found in the soluble fraction.
- Structural differences in Aβ42 fibrils may influence their interaction with diagnostic tracers like AV-45.
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