# Does amyloid fibril nucleation occur at surfaces only?

## TL;DR

This study explores how amyloid fibrils form, suggesting that they mostly start at surfaces rather than in solution, which could help understand Alzheimer's disease better.

## Contribution

The paper reveals that homogeneous nucleation of Aβ42 fibrils is rare, emphasizing the role of surfaces in heterogeneous nucleation.

## Key findings

- Homogeneous primary nucleation of Aβ42 fibrils is rare in vitro.
- Heterogeneous nucleation at surfaces is the dominant mechanism for Aβ42 fibril formation.
- Surface adsorption reduces conformational space, aiding protein folding.

## Abstract

The Aβ42 peptide (APP(672–713)), associated with Alzheimer disease, is highly prone to form amyloid fibrils and has been extensively studied through in vitro experiments. Such experiments represent a basis for understanding the biophysical chemistry of amyloid-related diseases. In this communication, we show that homogeneous primary nucleation in vitro of Aβ42 fibrils is a very rare event, implying that primary nucleation occurs almost exclusively at interfaces, by heterogeneous nucleation. Recognizing that the protein molecules in amyloid fibrils possess a two-dimensional fold, we discuss the nucleation in relation to protein folding and Levinthal’s paradox. In the much more rapid heterogeneous nucleation, we suggest that one catalyzing effect is the significant reduction of the effective conformational space when a monomer polypeptide chain (strongly) adsorbs to a surface, facilitating its search for the target fold.