Amyloid beta-protein induced electrophysiological changes are dependent on aggregation state: N-methyl-D-aspartate (NMDA) versus non-NMDA receptor/channel activation.
Amyloid beta-protein induced electrophysiological changes are dependent on aggregation state: N-methyl-D-aspartate (NMDA) versus non-NMDA receptor/channel activation.
复制标题
β-淀粉样蛋白诱导的电生理变化取决于聚集状态：N-甲基-D-天冬氨酸 (NMDA) 与非 NMDA 受体/通道激活。
DOI：
10.1016/j.neulet.2004.05.060
复制
发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Hartley,DeanM
中科院分区：
文献类型：
--
作者：
Ye,Chianping;Walsh,DominicM;Selkoe,DennisJ;Hartley,DeanM
阿尔茨海默病（AD）是一种进行性神经退行性疾病，然而，驱动这种疾病的潜在机制尚不清楚。未探索的是不同Aβ组装体的时间依赖性产生可能是致病级联的基础，生物药理学上不同的结构与独特的生物靶标相互作用。因此，在AD的最早临床阶段期间突触功能的细微改变的存在可能由淀粉样β蛋白（Aβ）的可扩散组装介导。利用原代培养的新皮层，我们比较了两种不同的Aβ组装体（原纤维（PF）和原纤维（FB））诱导的突触反应，并首次证明神经元激活选择性地依赖于Aβ的组装状态。PF诱导的活性被N-甲基-D-天冬氨酸（NMDA）受体拮抗剂d-APV特异性减弱。相反，非NMDA谷氨酸受体拮抗剂，NBQX，优先减少FB诱导的活动。在支持下，从培养基中去除Mg 2+，这增强了NMDA通道，增加了PF或FB诱导的激活，但d-APV更有效地衰减PF诱导的兴奋性活动。这些结果表明，PF可能激活神经元不同的纤维和贷款支持的假设，前纤维组装的Aβ可能在AD型突触缺陷的发展中发挥重要作用。
Alzheimer’s disease (AD) is a progressive neurodegenerative disease, however, the underlying mechanism driving this condition is unknown. Unexplored is the possibility that the time-dependent generation of different Aβ assemblies may underlie the pathogenic cascade with biophysically distinct structures interacting with unique biological targets. Thus, the presence of subtle alterations in synaptic function during the earliest clinical phase of AD may be mediated by diffusible assemblies of the amyloid β-protein (Aβ). Using primary neocortical cultures, here we compare the synaptic responses induced by two different Aβ assemblies, protofibrils (PFs) and fibrils (FBs), and demonstrate for the first time that neuronal activation was selectively dependent on the assembly state of Aβ. PF-induced activity was specifically attenuated by the N-methyl-d-aspartate (NMDA) receptor antagonist, d-APV. In contrast, the non-NMDA glutamate receptor antagonist, NBQX, preferentially reduced FB-induced activity. In support, removal of Mg2+from the medium, which enhances NMDA channels, increased both PF- or FB-induced activation, but d-APV was more effective in attenuating PF-induced excitatory activity. These findings suggest that PFs may activate neurons differently than fibrils and lend support to the hypothesis that pre-fibrillar assemblies of Aβ may play an important role in the development of AD-type synaptic deficits.