Structural Changes of Amyloid β-Protein Fibrils on Neuronal Cells.

Area of Science:

• Neuroscience
• Biochemistry
• Structural Biology

Background:

• Alzheimer's disease pathogenesis involves amyloid-beta (Aβ) aggregation and neuronal damage.
• Neuronal cell membranes are implicated in Aβ self-aggregation.
• Previous studies showed Aβ fibrils on membranes (M-fibrils) and neuronal cells (C-fibrils) are more toxic than water-formed fibrils (W-fibrils).

Purpose of the Study:

• To investigate the structural changes of Aβ fibrils on living neuronal cells.
• To determine the relationship between Aβ fibril structure and cytotoxicity on neuronal cells.

Main Methods:

• Fourier-transform infrared attenuated total reflection spectroscopy to detect structural changes of Aβ fibrils on neuronal cells.
• Pulse-chase experiments with fluorescently labeled Aβ to track fibril formation and transitions.

Main Results:

• Early Aβ-(1-40) C-fibrils exhibited antiparallel β-sheet structures, transitioning to parallel β-sheets as deposition progressed.
• Aβ-(1-42) C-fibrils consistently maintained antiparallel β-sheet structures.
• Cytotoxicity correlated with the presence of antiparallel β-sheet structures, indicating their role in lasting cell damage.

Conclusions:

• The structural transition of Aβ fibrils on neuronal surfaces is influenced by the cellular environment.
• Antiparallel β-sheet structures in early Aβ fibrils attached to cell surfaces are cytotoxic.
• Targeting these early, antiparallel β-sheet-containing fibrils presents a promising therapeutic strategy for Alzheimer's disease.