Peters Christian, Espinoza María Paz, Gallegos Scarlet, Opazo Carlos, Aguayo Luis G
Laboratory of Neurophysiology, Department of Physiology, Universidad de Concepción, Concepción, Chile.
Oxidation Biology Laboratory, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia.
Neurobiol Aging. 2015 Mar;36(3):1369-77. doi: 10.1016/j.neurobiolaging.2014.11.019. Epub 2014 Dec 16.
A major feature of Alzheimer's disease is the accumulation of β-amyloid (Aβ) peptide in the brain. Recent studies have indicated that Aβ oligomers (Aβo) can interact with the cellular prion protein (PrPc). Therefore, this interaction might be driving some of Aβ toxic effects in the synaptic region. In the present study, we report that Aβo binds to PrPc in the neuronal membrane playing a role on toxic effects induced by Aβ. Phospholipase C-enzymatic cleavage of PrPc from the plasma membrane attenuated the association of Aβo to the neurons. Furthermore, an anti-PrP antibody (6D11) decreased the association of Aβo to hippocampal neurons with a concomitant reduction in Aβo and PrPc co-localization. Interestingly, this antibody blocked the increase in membrane conductance and intracellular calcium induced by Aβo. Thus, the data indicate that PrPc plays a role on the membrane perforations produced by Aβo, the increase in calcium ions and the release of synaptic vesicles that subsequently leads to synaptic failure. Future studies blocking Aβo interaction with PrPc could be important for the discovery of new therapeutic strategies for Alzheimer's disease.
阿尔茨海默病的一个主要特征是大脑中β-淀粉样蛋白（Aβ）肽的积累。最近的研究表明，Aβ寡聚体（Aβo）可与细胞朊蛋白（PrPc）相互作用。因此，这种相互作用可能是Aβ在突触区域产生某些毒性作用的原因。在本研究中，我们报告Aβo与神经元膜中的PrPc结合，在Aβ诱导的毒性作用中发挥作用。从质膜上通过磷脂酶C酶切PrPc可减弱Aβo与神经元的结合。此外，一种抗PrP抗体（6D11）减少了Aβo与海马神经元的结合，同时Aβo和PrPc的共定位也减少。有趣的是，该抗体阻断了Aβo诱导的膜电导增加和细胞内钙增加。因此，数据表明PrPc在Aβo产生的膜穿孔、钙离子增加以及随后导致突触功能障碍的突触小泡释放中发挥作用。未来阻断Aβo与PrPc相互作用的研究对于发现阿尔茨海默病的新治疗策略可能很重要。
