Toxic Amyloid Tape: A Novel Mixed Antiparallel/Parallel β-Sheet Structure Formed by Amyloid β-Protein on GM1 Clusters

Area of Science:

• Neuroscience
• Biochemistry
• Structural Biology

Background:

• Alzheimer's disease pathogenesis involves abnormal amyloid beta-protein (Aβ) aggregation.
• Membrane-mediated amyloidogenesis, particularly on GM1 clusters, yields more toxic Aβ fibrils than those in aqueous solution.

Purpose of the Study:

• To elucidate the detailed structure of toxic Aβ-(1-40) fibrils formed on GM1 clusters.
• To compare the structure of toxic fibrils with less-toxic fibrils formed in aqueous solution.

Main Methods:

• Atomic force microscopy (AFM) for morphology analysis.
• Isotope-edited infrared spectroscopy for secondary structure determination.
• Chemical cross-linking and solid-state NMR for detailed structural investigation.

Main Results:

• Toxic fibrils exhibit a flat, tape-like morphology composed of a single β-sheet layer.
• Isotope-edited IR spectroscopy confirmed the inclusion of nearly the entire Aβ sequence in the β-sheet.
• Cross-linking and NMR data suggest toxic fibrils contain both in-register parallel and two-residue-shifted antiparallel β-sheet structures.

Conclusions:

• The toxic Aβ fibrils formed on GM1 clusters possess a novel and unique structure.
• This unique structure likely contributes to the increased toxicity of membrane-associated amyloid aggregates in Alzheimer's disease.