Soluble prion protein inhibits amyloid-β (Aβ) fibrillization and toxicity.
The pathogenesis of Alzheimer disease appears to be strongly linked to the aggregation of amyloid-β (Aβ) peptide and, especially, formation of soluble Aβ1-42 oligomers. It was recently demonstrated that the cellular prion protein, PrP(C), binds with high affinity to these oligomers, acting as a putative receptor that mediates at least some of their neurotoxic effects. Here we show that the soluble (i.e. glycophosphatidylinositol anchor-free) prion protein and its N-terminal fragment have a strong effect on the aggregation pathway of Aβ1-42, inhibiting its assembly into amyloid fibrils. Furthermore, the prion protein prevents formation of spherical oligomers that normally occur during Aβ fibrillogenesis, acting as a potent inhibitor of Aβ1-42 toxicity as assessed in experiments with neuronal cell culture. These findings may provide a molecular level foundation to explain the reported protective action of the physiologically released N-terminal N1 fragment of PrP(C) against Aβ neurotoxicity. They also suggest a novel approach to pharmacological intervention in Alzheimer disease.
Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Krzysztof
K
Nieznanski
Jin-Kyu
JK
Choi
Shugui
S
Chen
Krystyna
K
Surewicz
Witold K
WK
Surewicz
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry*; D045744:Cell Line, Tumor; D006801:Humans; D018625:Microscopy, Atomic Force / Q000379:methods; D009447:Neuroblastoma / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D011328:Prions / Q000737:chemistry; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D010455:Peptides; D011328:Prions