Postsynaptic kinase/phosphatase networks in amyloid beta-induced synaptic dysfunction

项目摘要 突触后激酶/磷酸酶网络在β淀粉样蛋白诱导的突触功能障碍中的作用 阿尔茨海默病（AD）的特征是突触功能受损和关键神经元突触丢失。 学习和记忆所需的前脑区域，包括海马。虽然病理因素， 导致AD的原因仍然存在争议（淀粉样蛋白β; Aβ与tau），有很强的遗传，生化，解剖学和 电生理学证据支持Aβ足以启动导致严重 突触病理学例如，亚微摩尔剂量的Aβ急性（在几分钟内）抑制长期 增强（LTP），一种对学习和记忆至关重要的突触可塑性形式。此外，较长的Aβ 暴露（数天至数周）导致抑郁症和兴奋性突触的消除， 这一过程需要NMDA受体信号传导。然而，驱动下行信号网络的 急性和慢性Aβ介导的突触病理学才刚刚开始出现，需要进一步研究。 研究了来自我们实验室的强有力的初步数据涉及几种突触后ser/thr激酶（CaMK II， DAPK 1，PKA）和磷酸酶（钙调神经磷酸酶（CaN））作为负责急性Aβ- 诱导LTP中断，可能通过受损的NMDA受体Ca 2+内流。目前还不清楚是否 这些相同的信号传导机制介导慢性Aβ诱导的突触抑制和消除， 这里公布的和初步的数据表明CaN活性是必需的。重要的是，所有这些 激酶和磷酸酶在突触后信号网络中相互作用， 事实上，PKA和CaN通过支架的突触锚定可以促进LTP或LT。 蛋白AKAP 79/150似乎对于促进PKA、CaN、DAPK 1和DAPK 1之间的信号传导串扰至关重要。 在突触位点的CaMK II，以建立正常的LTP/LTD平衡。在这个多PI项目中，我们将测试 假设Aβ通过干扰突触神经元引起急性（目的1和2）和慢性（目的3和4）突触功能障碍， 这种信号网络及其下游效应的平衡有利于LTD，导致LTP受损， 突触消除

Project Summary Abstract Postsynaptic kinase/phosphatase networks in amyloid β-induced synaptic dysfunction Alzheimer's disease (AD) is characterized by impaired synaptic function and synapse loss in key forebrain areas required for learning and memory, including the hippocampus. While the pathologic agent that causes AD remains contentious (amyloid-beta; Aβ vs. tau) there is strong genetic, biochemical, anatomical and electrophysiological evidence supporting that Aβ is sufficient to initiate cellular processes leading to severe synaptic pathology. For example sub-micromolar doses of Aβ acutely (within minutes) inhibit long-term potentiation (LTP), a form of synaptic plasticity critical for learning and memory. In addition, longer Aβ exposure (days to weeks) leads to depression and elimination of excitatory synapses through a process that requires NMDA receptor signaling. However, the downstream signaling networks that drive acute and chronic Aβ-mediated synaptic pathologies are only beginning to emerge and need to be further investigated. Strong preliminary data from our labs implicate several postsynaptic ser/thr kinases (CaMKII, DAPK1, PKA) and a phosphatase (calcineurin (CaN)) as key molecular players responsible for acute Aβ- induced LTP disruption, possibly through impaired NMDA receptor Ca2+ entry. It remains unclear whether these same signaling mechanisms mediate chronic Aβ-induced synaptic depression and elimination, but published and preliminary data presented here indicate that CaN activity is required. Importantly, all of these kinases and phosphatases interact with one another in a postsynaptic signaling network that integrates NMDAR activity to promote either LTP or LTD. Indeed, synaptic anchoring of PKA and CaN by the scaffold protein AKAP79/150 appears to be critical for promoting signaling crosstalk between PKA, CaN, DAPK1 and CaMKII at synaptic sites to establish normal LTP/LTD balance. In this multi-PI project we will test the hypothesis that Aβ causes acute (Aims 1 & 2) and chronic (Aims 3 & 4) synaptic dysfunction by perturbing the balance of this signaling network and its downstream effectors to favor LTD, leading to impaired LTP and synapse elimination.