Neuroserpin and transthyretin are extracellular chaperones that preferentially inhibit amyloid formation

Neuroserpin is a secreted protease inhibitor known to inhibit amyloid formation by the Alzheimer's beta peptide (A beta). To test whether this effect was constrained to AD, we used a range of in vitro assays to demonstrate that neuroserpin inhibits amyloid formation by several different proteins and protects against the associated cytotoxicity but, unlike other known chaperones, has a poor ability to inhibit amorphous protein aggregation. Collectively, these results suggest that neuroserpin has an unusual chaperone selectivity for intermediates on the amyloid-forming pathway. Bioinformatics analyses identified a highly conserved 14-residue region containing an alpha helix shared between neuroserpin and the thyroxine-transport protein transthyretin, and we subsequently demonstrated that transthyretin also preferentially inhibits amyloid formation. Last, we used rationally designed neuroserpin mutants to demonstrate a direct involvement of the conserved 14-mer region in its chaperone activity. Identification of this conserved region may prove useful in the future design of anti-amyloid reagents.

Automated summary

Neuroserpin has the ability to inhibit amyloid formation by multiple proteins and protect against associated cytotoxicity. It shows unique chaperone selectivity for intermediates on the amyloid-forming pathway, but has poor ability to inhibit amorphous protein aggregation. A conserved 14-residue region containing an alpha helix is identified, which may be useful in designing anti-amyloid reagents in the future.