Synthetic amyloid-beta oligomers impair long-term memory independently of cellular prion protein.
Inability to form new memories is an early clinical sign of Alzheimer's disease (AD). There is ample evidence that the amyloid-beta (Abeta) peptide plays a key role in the pathogenesis of this disorder. Soluble, bio-derived oligomers of Abeta are proposed as the key mediators of synaptic and cognitive dysfunction, but more tractable models of Abeta-mediated cognitive impairment are needed. Here we report that, in mice, acute intracerebroventricular injections of synthetic Abeta(1-42) oligomers impaired consolidation of the long-term recognition memory, whereas mature Abeta(1-42) fibrils and freshly dissolved peptide did not. The deficit induced by oligomers was reversible and was prevented by an anti-Abeta antibody. It has been suggested that the cellular prion protein (PrP(C)) mediates the impairment of synaptic plasticity induced by Abeta. We confirmed that Abeta(1-42) oligomers interact with PrP(C), with nanomolar affinity. However, PrP-expressing and PrP knock-out mice were equally susceptible to this impairment. These data suggest that Abeta(1-42) oligomers are responsible for cognitive impairment in AD and that PrP(C) is not required.
Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Milan 20156, Italy.
Claudia
C
Balducci
Marten
M
Beeg
Matteo
M
Stravalaci
Antonio
A
Bastone
Alessandra
A
Sclip
Emiliano
E
Biasini
Laura
L
Tapella
Laura
L
Colombo
Claudia
C
Manzoni
Tiziana
T
Borsello
Roberto
R
Chiesa
Marco
M
Gobbi
Mario
M
Salmona
Gianluigi
G
Forloni
D000544:Alzheimer Disease / Q000209:etiology; D016229:Amyloid beta-Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D003072:Cognition Disorders / Q000209:etiology / Q000378:metabolism; D006801:Humans; D007276:Injections, Intraventricular; D008297:Male; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018621:PrPC Proteins / Q000378:metabolism*; D000072002:Prion Proteins; D011328:Prions / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D020349:Surface Plasmon Resonance
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D018621:PrPC Proteins; D000072002:Prion Proteins; D011328:Prions; C512657:Prnp protein, mouse; C075222:amyloid beta-protein (1-42)