Massachusetts Institute of Technology, Cambridge, MA, USA.
J Alzheimers Dis. 2014;38(2):227-44. doi: 10.3233/JAD-130950.
Soluble oligomeric species of amyloid-β (Aβ) peptide are presumed to be drivers of synaptic impairment, and the resulting cognitive dysfunction in Alzheimer's disease. In 2009, cellular prion protein (PrPC) was identified in a genome-wide screen as a high-affinity receptor for Aβ oligomers, and since then, many studies have explored the role of PrPC in Alzheimer's disease. Herein, I systematically assess the current level of target validation for PrPC in Alzheimer's disease and the merits of the identified approaches to therapeutically affect the PrPC:Aβ oligomer-interaction. The interaction of Aβ oligomers with PrPC in mice impairs hippocampal long-term potentiation, memory, and learning in a manner that involves Fyn, tau, and glutamate receptors. Furthermore, PrPC acts to catalyze the formation of certain Aβ oligomeric species in the synapse and may mediate the toxic effects of other β-sheet rich oligomers as well. Therapeutic approaches utilizing soluble PrPC ectodomain or monoclonal antibodies targeting PrPC can at least partially prevent the neurotoxic effects of Aβ oligomers in mice.
可溶性寡聚体形式的淀粉样蛋白-β (Aβ) 肽被认为是突触损伤的驱动因素，也是阿尔茨海默病认知功能障碍的原因。2009 年，朊病毒蛋白 (PrPC) 在全基因组筛选中被鉴定为 Aβ 寡聚体的高亲和力受体，此后，许多研究探索了 PrPC 在阿尔茨海默病中的作用。在此，我系统地评估了目前针对阿尔茨海默病中 PrPC 的靶点验证水平，以及鉴定出的针对 PrPC:Aβ 寡聚体相互作用的治疗方法的优点。在小鼠中，Aβ 寡聚体与 PrPC 的相互作用以涉及 Fyn、tau 和谷氨酸受体的方式损害海马长时程增强、记忆和学习。此外，PrPC 可催化突触中某些 Aβ 寡聚体的形成，并可能介导其他富含β-折叠的寡聚体的毒性作用。利用可溶性 PrPC 细胞外结构域或针对 PrPC 的单克隆抗体的治疗方法至少可以部分预防 Aβ 寡聚体在小鼠中的神经毒性作用。
