Soluble prion protein and its N-terminal fragment prevent impairment of synaptic plasticity by Aβ oligomers: Implications for novel therapeutic strategy in Alzheimer's disease

Neurobiology of Disease

Witold K. Surewicz¹  Krzysztof Nieznanski²  Krystyna Surewicz³  Vernon A. Ruffin³  Jin-Kyu Choi³  Ahlam I. Salameh³  Jonah J. Scott-McKean⁴  Alberto C.S. Costa⁴ 

[1] Department of Psychiatry, Case Western Reserve University, Cleveland, OH 44116, USA;Department of Biochemistry, Nencki Institute of Experimental Biology, 02-093 Warsaw, Poland;Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH 44116, USA;Division of Pediatric Neurology, Department of Pediatrics, Case Western Reserve University, Cleveland, OH 44116, USA;

关键词: Alzheimer's disease;    Amyloid-beta (Aβ);    Prion protein;    Synaptic plasticity;    Long-term potentiation;    Cytotoxicity;   

DOI  :  

来源: DOAJ

【 摘 要 】

The pathogenic process in Alzheimer's disease (AD) appears to be closely linked to the neurotoxic action of amyloid-β (Aβ) oligomers. Recent studies have shown that these oligomers bind with high affinity to the membrane-anchored cellular prion protein (PrPC). It has also been proposed that this binding might mediate some of the toxic effects of the oligomers. Here, we show that the soluble (membrane anchor-free) recombinant human prion protein (rPrP) and its N-terminal fragment N1 block Aβ oligomers-induced inhibition of long-term potentiation (LTP) in hippocampal slices, an important surrogate marker of cognitive deficit associated with AD. rPrP and N1 are also strikingly potent inhibitors of Aβ cytotoxicity in primary hippocampal neurons. Furthermore, experiments using hippocampal slices and neurons from wild-type and PrPC null mice (as well as rat neurons in which PrPC expression was greatly reduced by gene silencing) indicate that, in contrast to the impairment of synaptic plasticity by Aβ oligomers, the cytotoxic effects of these oligomers, and the inhibition of these effects by rPrP and N1, are independent of the presence of endogenous PrPC. This suggests fundamentally different mechanisms by which soluble rPrP and its fragments inhibit these two toxic responses to Aβ. Overall, these findings provide strong support to recent suggestions that PrP-based compounds may offer new avenues for pharmacological intervention in AD.

【 授权许可】

Unknown