Background: NAC is a 35-amino-acid peptide which has been isolated from the insoluble core of Alzheimer's disease (AD) amyloid plaque. It is a fragment of α-synuclein or (NACP), a neuronal protein of unknown function. We noted a striking sequence similarity between NAC, the carboxyl terminus of the β-amyloid protein, and a region of the scrapie prion protein (PrP) which has been implicated in amyloid formation. Results: NAC was preprared by chemical synthesis and was found to form amuloid fibrils via a nucleotion-dependent polymerization mechanism. NAC amyloid fibrils effectively seed β1-40 amyloid ormation. Amyloid fibrils comprising peptide models of the homologous β and PrP sequences were also found to seed amyloid formation by NAC. Conclusions: The in vitro model studies presented here suggest that seeding of NAC amyloid formation by the β-amyloid protein, or seeding of amyloid fibrils of the β-amyloid protein by NAC, may occur in vivo. Accumulation of ordered NAC aggregates in the synapse may be responsible for the neurodegeneration observed in AD and the prion disorders. Alternatively, neurodegeneration may be caused by the loss of α-synuclein (NACP) function.
Bibliographical noteFunding Information:
Ackwolule~~er,~eu~ts: We thank the MIT Biopolymers Laboratory for quantitative amino acid analysis and amino acid sequencing and Anna Poon for electron microscopy.This work was supported by the National Institutes of Health (Grant AGOX470) and the National Science Foundation (Presidential Young Investigator Award with matching funds from Genentech, Merck, and Upjohn). P.T.L. is the Firmenich Associate Professor of Chemistry. l?H.W. was a 1994 American Chemical Society IIivision Medicinal Chemistry Fellow (sponsored by Eli Lilly).
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Drug Discovery
- Clinical Biochemistry