Neurobiology of Disease Soluble -amyloid 1– 40 Induces Nmda-dependent Degradation of Postsynaptic Density-95 at Glutamatergic Synapses
Neurobiology of Disease Soluble -amyloid 1– 40 Induces Nmda-dependent Degradation of Postsynaptic Density-95 at Glutamatergic Synapses
复制标题
DOI：
--
复制
发表时间：
--
期刊：
影响因子：
--
通讯作者：
F. Roselli;M. Tirard;J. Lu;P. Hutzler;P. Lamberti;P. Livrea;M. Morabito;O. F. X. Almeida
中科院分区：
文献类型：
--
作者：
F. Roselli;M. Tirard;J. Lu;P. Hutzler;P. Lamberti;P. Livrea;M. Morabito;O. F. X. Almeida
淀粉样蛋白- (A) 与早期阿尔茨海默病中观察到的记忆丧失和突触可塑性破坏有关。最近，研究表明可溶性 A 寡聚物以培养的大鼠海马神经元中的突触为目标，表明 A 在调节突触结构和功能中具有直接作用。突触后密度 95 (PSD-95) 是一种突触后支架蛋白，在突触可塑性以及突触处 AMPA (AMPAR) 和 NMDA (NMDAR) 受体的稳定中发挥关键作用。在这里，我们表明，将培养的皮层神经元暴露于可溶性 A 1–40 寡聚物中，会以剂量和时间依赖性方式降低 PSD-95 蛋白水平，并且 A1 1–40 依赖性 PSD-95 降低需要 NMDAR 活性。我们还表明 PSD-95 的减少需要细胞周期蛋白依赖性激酶 5 活性并涉及蛋白酶体途径。对皮层培养神经元的免疫染色分析表明，A 治疗会导致突触处的 PSD-95 和 AMPAR 谷氨酸受体亚基 2 的表面表达同时降低。 总之，这些数据表明 A 触发突触功能障碍的新途径，即通过改变谷氨酸能突触的分子组成。
Amyloid- (A) has been implicated in memory loss and disruption of synaptic plasticity observed in early-stage Alzheimer's disease. Recently, it has been shown that soluble A oligomers target synapses in cultured rat hippocampal neurons, suggesting a direct role of A in the regulation of synaptic structure and function. Postsynaptic density-95 (PSD-95) is a postsynaptic scaffolding protein that plays a critical role in synaptic plasticity and the stabilization of AMPA (AMPARs) and NMDA (NMDARs) receptors at synapses. Here, we show that exposure of cultured cortical neurons to soluble oligomers of A 1– 40 reduces PSD-95 protein levels in a dose-and time-dependent manner and that the A1 1– 40-dependent decrease in PSD-95 requires NMDAR activity. We also show that the decrease in PSD-95 requires cyclin-dependent kinase 5 activity and involves the proteasome pathway. Immunostaining analysis of cortical cultured neurons revealed that A treatment induces concomitant decreases in PSD-95 at synapses and in the surface expression of the AMPAR glutamate receptor subunit 2. Together, these data suggest a novel pathway by which A triggers synaptic dysfunction, namely, by altering the molecular composition of glutamatergic synapses.