The prion protein (PrP) is best known for its association with prion diseases. However, a controversial new role for PrP in Alzheimer disease (AD) has recently emerged. In vitro studies and mouse models of AD suggest that PrP may be involved in AD pathogenesis through a highly specific interaction with amyloid- (A42) oligomers. Immobilized recombinant human PrP (huPrP) also exhibited high affinity and specificity for A42 oligomers. Here we report the novel finding that aggregated forms of huPrP and A42 are co-purified from AD brain extracts. Moreover, an anti-PrP antibody and an agent that specifically binds to insoluble PrP (iPrP) co-precipitate insoluble A from human AD brain. Finally, using peptide membrane arrays of 99 13-mer peptides that span the entire sequence of mature huPrP, two distinct types of A binding sites on huPrP are identified in vitro. One specifically binds to A42 and the other binds to both A42 and A40. Notably, A42-specific binding sites are localized predominantly in the octapeptide repeat region, whereas sites that bind both A40 and A42 are mainly in the extreme N-terminal or C-terminal domains of PrP. Our study suggests that iPrP is the major PrP species that interacts with insoluble A42 in vivo. Although this work indicated the interaction of A42 with huPrP in the AD brain, the pathophysiological relevance of the iPrP/A42 interaction remains to be established. Alzheimer disease (AD)2 is the leading cause of dementia in the elderly and the most common neurodegenerative disorder. The underlying pathology in AD seems to be associated with the accumulation of soluble and insoluble aggregated species of the amyloid- (A) peptide in the brain (1). However, the mechanisms underlying A deposition and neurotoxicity remain poorly understood. The cellular prion protein (PrP C ) is a glycoprotein highly expressed in the brain, and best known for its association with prion diseases. These are unique neurodegenerative disorders with an infectious, sporadic or genetic etiology, and which are characterized by deposition of misfolded, pathological PrP (PrP Sc ) in the brain (2). Interestingly, a recent interpretation of early and newer observations suggests that PrP C may play a role in the pathogenesis of AD (3). Epidemiological studies suggest that the Met/Val polymorphism at residue 129 in PrP modulates the number of A deposits (4). Also, pathological evidence indicates that PrP deposits often accompany A plaques in AD (5-7). Moreover, transgenic mice expressing mutant amyloid precursor protein (APP) and overexpressing hamster PrP C present an exacerbated A plaque burden (8). The circumstantial evidence of an association between PrP and A was greatly strengthened by the recent finding that PrP was the protein that most strongly supported the binding of cells to soluble A42 oligomers in a screen of 225,000 murine clones (9). The authors also showed that although A42 oligomers suppressed long-term potentiation (LTP) in CA1 hippocampal neurons in mouse brain slices, LTP inhibitio...
Recent advances in the regulation of histone lysine methylation in plants and the role of this modification in the developmental programming of Arabidopsis are discussed.
Prion diseases are associated with the conformational conversion of the cellular prion protein (PrPC) into the pathological scrapie isoform (PrPSc) in the brain. Both the in vivo and in vitro conversion of PrPC into PrPSc is significantly inhibited by differences in amino acid sequence between the two molecules. Using protein misfolding cyclic amplification (PMCA), we now report that the recombinant full-length human PrP (rHuPrP23-231) (that is unglycosylated and lacks the glycophosphatidylinositol anchor) is a strong inhibitor of human prion propagation. Furthermore, rHuPrP23-231 also inhibits mouse prion propagation in a scrapie-infected mouse cell line. Notably, it binds to PrPSc, but not PrPC, suggesting that the inhibitory effect of recombinant PrP results from blocking the interaction of brain PrPC with PrPSc. Our findings suggest a new avenue for treating prion diseases, in which a patient's own unglycosylated and anchorless PrP is used to inhibit PrPSc propagation without inducing immune response side effects.
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