阿尔茨海默氏症患者脑细胞内PrP与Aβ低聚物结合

（图片来源：Thomas Deerinck NCMIR/Science Photo Library）

哺乳动物的prion蛋白PrP是细胞表面的糖蛋白,与许多神经退行性疾病有关。一般认为可溶性淀粉状-β肽低聚物在阿尔茨海默氏症中起中心作用的假说已被很多人接受，但尚没有关于Aβ低聚物影响神经元的机制基础的介绍。

来自几个方面的证据表明，对神经元上的可溶性Aβ低聚物来说，存在一种高亲和力细胞表面受体，它在阿尔茨海默氏症病理中起中心作用，而现在，细胞锯蛋白PrP^c已被发现是这种作用的一个候选分子。PrP是与“脂质筏”相关的一种胞质膜糖蛋白，以高亲和力选择性地结合Aβ低聚物，调控这种肽的有害效应。这些数据提出一个可能性：PrP^c -特异性药物也许对阿尔茨海默氏症有疗效，而且它们还表明传染性锯蛋白疾病与阿尔茨海默氏症之间有一个出乎意料的联系。

推荐原始出处：

Nature 457, 1128-1132 (26 February 2009) | doi:10.1038/nature07761

Cellular prion protein mediates impairment of synaptic plasticity by amyloid-β oligomers

Juha Laurén1, David A. Gimbel1, Haakon B. Nygaard1, John W. Gilbert1 & Stephen M. Strittmatter1

Cellular Neuroscience, Neurodegeneration and Repair Program, Yale University School of Medicine, New Haven, Connecticut 06536, USA

Correspondence to: Stephen M. Strittmatter1 Correspondence and requests for materials should be addressed to S.M.S.

A pathological hallmark of Alzheimer's disease is an accumulation of insoluble plaque containing the amyloid-β peptide of 40–42 amino acid residues1. Prefibrillar, soluble oligomers of amyloid-β have been recognized to be early and key intermediates in Alzheimer's-disease-related synaptic dysfunction2, 3, 4, 5, 6, 7, 8, 9. At nanomolar concentrations, soluble amyloid-β oligomers block hippocampal long-term potentiation7, cause dendritic spine retraction from pyramidal cells5, 8 and impair rodent spatial memory2. Soluble amyloid- oligomers have been prepared from chemical syntheses, transfected cell culture supernatants, transgenic mouse brain and human Alzheimer's disease brain2, 4, 7, 9. Together, these data imply a high-affinity cell-surface receptor for soluble amyloid- oligomers on neurons—one that is central to the pathophysiological process in Alzheimer's disease. Here we identify the cellular prion protein (PrP^c) as an amyloid-β-oligomer receptor by expression cloning. Amyloid- oligomers bind with nanomolar affinity to PrP^c, but the interaction does not require the infectious PrP^Sc conformation. Synaptic responsiveness in hippocampal slices from young adult PrP null mice is normal, but the amyloid-β oligomer blockade of long-term potentiation is absent. Anti-PrP antibodies prevent amyloid-β-oligomer binding to PrP^c and rescue synaptic plasticity in hippocampal slices from oligomeric amyloid-β. Thus, PrP^c is a mediator of amyloid-β-oligomer-induced synaptic dysfunction, and PrP^c-specific pharmaceuticals may have therapeutic potential for Alzheimer's disease.