A Solvatochromic Near Infrared Fluorophore Sensitive to the Full Amyloid Beta Aggregation Pathway
Zeming Wang1, Line G Kristensen1,2, Yen H Ho1,3
1The Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, California 94720, United States.
Journal of the American Chemical Society
|May 23, 2025
Summary
A novel near-infrared fluorophore tracks amyloid beta (Aβ42) aggregation in real-time, revealing early-stage oligomer formation and plaque development. This method offers minimally invasive insights into Alzheimer's disease pathology.
Area of Science:
- Biochemistry
- Neuroscience
- Materials Science
Background:
- Alzheimer's disease is linked to amyloid beta (Aβ42) plaque aggregation.
- Early-stage soluble Aβ42 oligomers are implicated in neurodegeneration.
- Understanding Aβ42 aggregation mechanisms and early structures remains challenging.
Purpose of the Study:
- To develop a method for tracking Aβ42 aggregation from early oligomers to plaques.
- To investigate the formation and growth mechanisms of Aβ42 aggregates.
- To provide real-time, minimally invasive insights into the Aβ42 aggregation pathway.
Main Methods:
- Utilized a solvatochromic fluorophore (Phazr-N3) with near-infrared emission.
- Monitored environment-sensitive spectral shifts during synthetic Aβ42 aggregation.
- Employed solution anisotropy and spectral imaging for aggregate analysis.
Main Results:
- Phazr-N3 tracked Aβ42 aggregation through spectral shifts, preceding thioflavin T changes.
- Real-time measurements indicated rapid liquid-liquid phase separation and slow dehydration.
- High Phazr-N3 fluorescence intensity observed in synthetic plaques, even with cellular and protein interference.
Conclusions:
- Phazr-N3 enables real-time monitoring of the entire Aβ42 aggregation process.
- The probe's structure-independent binding to free Aβ42 facilitates early-stage detection.
- This approach offers a powerful tool for studying Alzheimer's disease pathogenesis.
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03:03Amyloid Fibrils
Amyloid fibrils are aggregates of misfolded proteins. Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils.
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining, normally used to...
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining, normally used to...
03:03Amyloid Fibrils
Amyloid fibrils are aggregates of misfolded proteins. Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils.
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining, normally used to...
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining, normally used to...