Soluble oligomers of A42 peptide are believed to play a major role in the pathogenesis of Alzheimer disease (AD). It was recently found that at least some of the neurotoxic effects of these oligomers may be mediated by specific binding to the prion protein, PrP C , on the cell surface (Laurén, J., Gimbel, D. A., Nygaard, H. B., Gilbert, J. W., and Strittmatter, S. M. (2009) Nature 457, 1128 -1132). Here we characterized the interaction between synthetic A42 oligomers and the recombinant human prion protein (PrP) using two biophysical techniques: site-directed spin labeling and surface plasmon resonance. Our data indicate that this binding is highly specific for a particular conformation adopted by the peptide in soluble oligomeric species. The binding appears to be essentially identical for the Met 129 and Val 129 polymorphic forms of human PrP, suggesting that the role of PrP codon 129 polymorphism as a risk factor in AD is due to factors unrelated to the interaction with A oligomers. It was also found that in addition to the previously identified ϳ95-110 segment, the second region of critical importance for the interaction with A42 oligomers is a cluster of basic residues at the extreme N terminus of PrP (residues 23-27). The deletion of any of these segments results in a major loss of the binding function, indicating that these two regions likely act in concert to provide a high affinity binding site for A42 oligomers. This insight may help explain the interplay between the postulated protective and pathogenic roles of PrP in AD and may contribute to the development of novel therapeutic strategies as well.
Alzheimer disease (AD)2 is a devastating age-related neurodegenerative disorder leading to memory loss and progressive decline in cognitive ability (1-3). Pathologically, the disease is characterized by the formation of neurofibrillary tangles composed of hyperphosphorylated Tau and accumulation of extracellular amyloid plaques (1-6). The main component of these plagues is the 40 -42-amino acid residue amyloid- (A) peptide, a product of proteolytic processing of a large membrane glycoprotein, amyloid precursor protein (APP).Although the etiology of AD remains poorly understood, the leading hypothesis is that the major causative agent is the aggregated form of A (4, 7). Although in the past much attention has focused on mature -sheet-rich amyloid fibrils, more recent evidence points to a critical role of smaller, soluble A oligomers (8 -13). In contrast to poor quantitative correlation between the burden of insoluble fibrillar amyloid plagues and the degree of dementia, the severity of AD appears to correlate well with the concentration of soluble A oligomers (9 -11). Furthermore, these soluble oligomers have been shown to be potent neurotoxins in vitro and in vivo; among other effects, they were reported to inhibit hippocampal long term potentiation, a widely used electrophysiological measure of synaptic plasticity related to learning and memory, and cause impairment of long term memory in rats (...