Differentiating Alzheimer's Aβ Isoforms Coaggregated in Cerebrospinal Fluid via Single-Particle Imaging
Lily Henry1, Shayon Bhattacharya2, Talia Bergaglio1
1Transport at Nanoscale Interfaces Laboratory, Swiss Federal Laboratories for Materials Science and Technology, Dübendorf CH-8600, Switzerland.
Abstract:
Amyloid polymorphism can reflect Alzheimer's disease (AD) stages. This paper demonstrates that amyloid β (Aβ) peptides, primarily Aβ-40 and Aβ-42 (implicated in AD pathology), present in cerebrospinal fluid (CSF), can be differentiated, and their morphology studied in detail using fluorescence-based super-resolution and atomic force microscopy (AFM). An inhibitory effect of Aβ-40 on Aβ-42 protein aggregation, marked by Aβ-40 oligomers colocalizing along the Aβ-42 fibril backbone, was resolved at the single-particle level. Molecular dynamics simulations revealed that coaggregation is modulated by the ionic environment in CSF, where calcium ions form bridges between Glu residues of Aβ-40 and Aβ-42, known to stabilize the fibril structure. This ion-mediated tethering compacts Aβ-40 and kinetically traps the fibril-oligomer interface, thus reducing fibril elongation. The isoform-specific imaging method further allowed us to distinguish Aβ-40 and Aβ-42 aggregates from oligomers to mature fibrils in the CSF of AD patients, and the nanoscopic differences in aggregate sizes were quantified from the AFM topographs. Such a protein characterization approach, which is not limited by analyte size or shape and is capable of fingerprinting Aβ aggregates in CSF, could be used in clinical settings to monitor the progression of Alzheimer's disease and related pathologies.
Insights
Alzheimer
Area of Science:
- Neuroscience
- Biochemistry
- Biophysics
Background:
- Amyloid polymorphism correlates with Alzheimer's disease (AD) stages.
- Amyloid-beta (Aβ) peptides, specifically Aβ-40 and Aβ-42, are central to AD pathology.
- Cerebrospinal fluid (CSF) contains Aβ peptides whose aggregation patterns may indicate disease progression.
Purpose of the Study:
- To differentiate and characterize the morphology of Aβ-40 and Aβ-42 peptides in CSF.
- To investigate the inhibitory effect of Aβ-40 on Aβ-42 aggregation at a single-particle level.
- To explore the role of the CSF ionic environment in modulating Aβ coaggregation.
Main Methods:
- Utilized fluorescence-based super-resolution microscopy and atomic force microscopy (AFM) for detailed Aβ morphology studies.
- Employed molecular dynamics simulations to understand the mechanisms of Aβ coaggregation.
- Developed an isoform-specific imaging method for distinguishing Aβ aggregate types in patient CSF.
Main Results:
- Resolved the inhibitory effect of Aβ-40 on Aβ-42 aggregation, with Aβ-40 oligomers observed on Aβ-42 fibril backbones.
- Identified calcium ions in CSF as key mediators, forming bridges between Aβ-40 and Aβ-42 that stabilize fibrils and reduce elongation.
- Quantified nanoscopic differences in Aβ aggregate sizes (oligomers to fibrils) from AFM data in AD patient CSF.
Conclusions:
- The developed protein characterization method can fingerprint Aβ aggregates in CSF, irrespective of size or shape.
- This approach enables the distinction of Aβ-40 and Aβ-42 aggregates, offering insights into AD.
- Potential clinical application for monitoring Alzheimer's disease progression and related pathologies through CSF Aβ analysis.
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