From Disordered to Ordered: Nanoscale Spectroscopy Reveals Structural Evolution of Amyloid Beta 40 Fibrils

Area of Science:

• Biochemistry
• Neuroscience
• Structural Biology

Background:

• Amyloid beta-40 (Aβ40) aggregation is central to Alzheimer's disease and cerebral amyloid angiopathy.
• The structural evolution of Aβ40 from early assemblies to mature fibrils is not fully understood.

Purpose of the Study:

• To characterize the morphological and structural heterogeneity of Aβ40 at the single-fibril level during aggregation.
• To elucidate the structural transitions and polymorphs involved in Aβ40 fibril maturation.

Main Methods:

• Atomic force microscopy coupled with infrared spectroscopy (AFM-IR) was used to analyze Aβ40 fibrils.
• Single-fibril analysis was performed across different aggregation stages.
• Seeding experiments with isotopically labeled Aβ40 were conducted.

Main Results:

• Early-stage Aβ40 fibrils displayed two distinct polymorphs with disordered structures and antiparallel beta-sheet motifs.
• Mature fibrils converged to a single dominant polymorph with parallel beta-sheet conformations.
• Disordered early-stage polymorphs were found to not propagate efficiently.

Conclusions:

• Early-stage antiparallel beta-sheet intermediates in Aβ40 aggregation are transient.
• Fibril maturation involves a transition from heterogeneous, disordered structures to a more homogeneous, parallel beta-sheet conformation.
• These findings provide mechanistic insights into amyloid polymorphism and therapeutic targeting for Aβ40-related diseases.