Synthetic amyloid-β oligomers impair long-term memory independently of cellular prion protein

被引:399
作者
Balducci, Claudia [1 ]
Beeg, Marten [2 ]
Stravalaci, Matteo [2 ]
Bastone, Antonio [2 ]
Sclip, Alessandra [1 ]
Biasini, Emiliano [1 ,3 ]
Tapella, Laura [1 ,3 ]
Colombo, Laura [2 ]
Manzoni, Claudia [2 ]
Borsello, Tiziana [1 ]
Chiesa, Roberto [1 ,3 ]
Gobbi, Marco [2 ]
Salmona, Mario [2 ]
Forloni, Gianluigi [1 ]
机构
[1] Mario Negri Inst Pharmacol Res, Dept Neurosci, I-20156 Milan, Italy
[2] Mario Negri Inst Pharmacol Res, Dept Mol Pharmacol & Biochem, I-20156 Milan, Italy
[3] Dulbecco Telethon Inst, I-20156 Milan, Italy
关键词
Alzheimer; neurotoxicity; object recognition test; surface plasmon resonance; protein aggregation; CENTRAL-NERVOUS-SYSTEM; ALZHEIMERS-DISEASE; SYNAPTIC PLASTICITY; RECOGNITION MEMORY; TRANSGENIC MICE; RECEPTOR TRAFFICKING; COGNITIVE FUNCTION; NATURAL OLIGOMERS; PEPTIDE-SYNTHESIS; MOLECULAR-BASIS;
D O I
10.1073/pnas.0911829107
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Inability to form new memories is an early clinical sign of Alzheimer's disease (AD). There is ample evidence that the amyloid-beta (A beta) peptide plays a key role in the pathogenesis of this disorder. Soluble, bio-derived oligomers of A beta are proposed as the key mediators of synaptic and cognitive dysfunction, but more tractable models of A beta-mediated cognitive impairment are needed. Here we report that, in mice, acute intracerebroventricular injections of synthetic A beta(1-42) oligomers impaired consolidation of the long-term recognition memory, whereas mature A beta(1-42) fibrils and freshly dissolved peptide did not. The deficit induced by oligomers was reversible and was prevented by an anti-A beta antibody. It has been suggested that the cellular prion protein (PrPC) mediates the impairment of synaptic plasticity induced by A beta. We confirmed that A beta(1-42) oligomers interact with PrPC, with nanomolar affinity. However, PrP-expressing and PrP knock-out mice were equally susceptible to this impairment. These data suggest that A beta(1-42) oligomers are responsible for cognitive impairment in AD and that PrPC is not required.
引用
收藏
页码:2295 / 2300
页数:6
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