Amyloid-β42 interacts mainly with insoluble prion protein in the Alzheimer brain

Wen Quan Zou, Xiangzhu Xiao, Jue Yuan, Gianfranco Puoti, Hisashi Fujioka, Xinglong Wang, Sandy Richardson, Xiaochen Zhou, Roger Zou, Shihao Li, Xiongwei Zhu, Patrick L. McGeer, John McGeehan, Geoff Kneale, Diego E. Rincon-Limas, Pedro Fernandez-Funez, Hyoung Gon Lee, Mark A. Smith, Robert B. Petersen, Jian Ping Guo

Research output: Contribution to journalArticlepeer-review

76 Scopus citations


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-β (Aβ42) oligomers. Immobilized recombinant human PrP (huPrP) also exhibited high affinity and specificity for Aβ42 oligomers. Here we report the novel finding that aggregated forms of huPrP and Aβ42 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 Aβ 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 Aβ binding sites on huPrP are identified in vitro. One specifically binds to Aβ42 and the other binds to both Aβ42 and Aβ40. Notably, Aβ42-specific binding sites are localized predominantly in the octapeptide repeat region, whereas sites that bind both Aβ40 and Aβ42 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 Aβ42 in vivo. Although this work indicated the interaction of Aβ42 with huPrP in the AD brain, the pathophysiological relevance of the iPrP/Aβ42 interaction remains to be established.

Original languageEnglish (US)
Pages (from-to)15095-15105
Number of pages11
JournalJournal of Biological Chemistry
Issue number17
StatePublished - Apr 29 2011


Dive into the research topics of 'Amyloid-β42 interacts mainly with insoluble prion protein in the Alzheimer brain'. Together they form a unique fingerprint.

Cite this