An N-terminal fragment of the prion protein binds to amyloid-β oligomers and inhibits their neurotoxicity in vivo.
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.
Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118.
Brian R
BR
Fluharty
Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118. Electronic address: biasini@bu.edu.
Emiliano
E
Biasini
Department of Molecular Biochemistry and Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milan, Italy.
Matteo
M
Stravalaci
Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milan, Italy.
Alessandra
A
Sclip
Department of Molecular Biochemistry and Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milan, Italy.
Luisa
L
Diomede
Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milan, Italy.
Claudia
C
Balducci
Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milan, Italy.
Pietro
P
La Vitola
Department of Molecular Biochemistry and Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milan, Italy.
Massimo
M
Messa
Department of Molecular Biochemistry and Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milan, Italy.
Laura
L
Colombo
Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milan, Italy.
Gianluigi
G
Forloni
Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milan, Italy.
Tiziana
T
Borsello
Department of Molecular Biochemistry and Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milan, Italy.
Marco
M
Gobbi
Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118.
David A
DA
Harris
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D058227:Amyloidogenic Proteins / Q000737:chemistry; D000818:Animals; D052160:Benzothiazoles; D017173:Caenorhabditis elegans / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D019636:Neurodegenerative Diseases / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D011328:Prions / Q000737:chemistry*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D020349:Surface Plasmon Resonance; D013569:Synapses / Q000378:metabolism; D013844:Thiazoles / Q000737:chemistry
D016229:Amyloid beta-Peptides; D058227:Amyloidogenic Proteins; D052160:Benzothiazoles; D010455:Peptides; D011328:Prions; D013844:Thiazoles; C009462:thioflavin T