The core Alzheimer's peptide NAC forms amyloid fibrils which seed and are seeded by beta-amyloid: is NAC a common trigger or target in neurodegenerative disease?
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 alpha-synuclein (or NACP), a neuronal protein of unknown function. We noted a striking sequence similarity between NAC, the carboxyl terminus of the beta-amyloid protein, and a region of the scrapie prion protein (PrP) which has been implicated in amyloid formation.


RESULTS
NAC was prepared by chemical synthesis and was found to form amyloid fibrils via a nucleation-dependent polymerization mechanism. NAC amyloid fibrils effectively seed beta 1-40 amyloid formation. Amyloid fibrils comprising peptide models of the homologous beta 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 beta-amyloid protein, or seeding of amyloid fibrils of the beta-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 alpha-synuclein (NACP) function.
Han
H
H
Department of Chemistry, Massachusetts Institute of Technology, Cambridge 02139, USA.
Weinreb
P H
PH
Lansbury
P T
PT
D000595:Amino Acid Sequence; D000682:Amyloid / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003460:Crystallization; D006801:Humans; D007700:Kinetics; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D009410:Nerve Degeneration / Q000378:metabolism*; D009419:Nerve Tissue Proteins; D012995:Solubility; D012996:Solutions; D017550:Spectroscopy, Fourier Transform Infrared; D013569:Synapses / Q000378:metabolism; D051843:Synucleins; D051844:alpha-Synuclein
D000682:Amyloid; D016229:Amyloid beta-Peptides; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; D012996:Solutions; D051843:Synucleins; D051844:alpha-Synuclein