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      An N-terminal Fragment of the Prion Protein Binds to Amyloid-β Oligomers and Inhibits Their Neurotoxicity in Vivo*

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          Abstract

          Background: The cellular prion protein (PrP C) could be a toxicity-transducing receptor for amyloid-β (Aβ) oligomers.

          Results: N1, a naturally occurring fragment of PrP C, binds Aβ oligomers, inhibits their polymerization into fibrils, and suppresses their neurotoxic effects in vitro and in vivo.

          Conclusion: N1 binds tightly to Aβ oligomers and blocks their neurotoxicity.

          Significance: Administration of exogenous N1 or related peptides may represent an effective therapy for Alzheimer disease.

          Abstract

          A hallmark of Alzheimer disease (AD) is the accumulation of the amyloid-β (Aβ) peptide in the brain. Considerable evidence suggests that soluble Aβ oligomers are responsible for the synaptic dysfunction and cognitive deficit observed in AD. However, the mechanism by which these oligomers exert their neurotoxic effect remains unknown. Recently, it was reported that Aβ oligomers bind to the cellular prion protein with high affinity. Here, we show that N1, the main physiological cleavage fragment of the cellular prion protein, is necessary and sufficient for binding early oligomeric intermediates during Aβ polymerization into amyloid fibrils. The ability of N1 to bind Aβ oligomers is influenced by positively charged residues in two sites (positions 23–31 and 95–105) and is dependent on the length of the sequence between them. Importantly, we also show that N1 strongly suppresses Aβ oligomer toxicity in cultured murine hippocampal neurons, in a Caenorhabditis elegans-based assay, and in vivo in a mouse model of Aβ-induced memory dysfunction. These data suggest that N1, or small peptides derived from it, could be potent inhibitors of Aβ oligomer toxicity and represent an entirely new class of therapeutic agents for AD.

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          Author and article information

          Journal
          J Biol Chem
          J. Biol. Chem
          jbc
          jbc
          JBC
          The Journal of Biological Chemistry
          American Society for Biochemistry and Molecular Biology (9650 Rockville Pike, Bethesda, MD 20814, U.S.A. )
          0021-9258
          1083-351X
          15 March 2013
          28 January 2013
          28 January 2013
          : 288
          : 11
          : 7857-7866
          Affiliations
          From the []Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118 and
          the Departments of [§ ]Molecular Biochemistry and Pharmacology and
          []Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milan, Italy
          Author notes
          [2 ] To whom correspondence should be addressed: Dept. of Biochemistry, Boston University School of Medicine, 72 East Concord St., Boston, MA 02118. Tel.: 617-638-4048; Fax: 617-638-4067; E-mail: biasini@ 123456bu.edu .
          [1]

          Both authors contributed equally to this work.

          Article
          M112.423954
          10.1074/jbc.M112.423954
          3597823
          23362282
          6bd064f0-db93-4939-8d4b-c15eb3652f0a
          © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.

          Author's Choice—Final version full access.

          Creative Commons Attribution Non-Commercial License applies to Author Choice Articles

          History
          : 28 September 2012
          : 15 January 2013
          Funding
          Funded by: National Institutes of Health
          Award ID: R01 NS065244
          Award ID: R01 NS040975
          Categories
          Molecular Bases of Disease

          Biochemistry
          alzheimer disease,amyloid,neurodegeneration,neuroprotection,prions
          Biochemistry
          alzheimer disease, amyloid, neurodegeneration, neuroprotection, prions

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