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

项目摘要摘要 突触后激酶/磷酸酶网络与淀粉样蛋白β诱导的突触功能障碍 阿尔茨海默病(AD)的特点是突触功能受损和突触丢失。 学习和记忆所需的前脑区域，包括海马体。而这一病原体 导致阿尔茨海默病的原因仍然存在争议(淀粉样β蛋白；Aβ与tau)有很强的遗传、生化、解剖和 电生理学证据支持β足以启动细胞过程导致严重的 突触病理学。例如，亚微摩尔剂量的β(在几分钟内)会强烈地抑制长期的 增强(LTP)，突触可塑性的一种形式，对学习和记忆至关重要。此外，更长的Aβ 暴露(几天到几周)会导致抑郁，并通过一种 需要NMDA受体信号的过程。然而，驱动的下游信令网络 急性和慢性A-β介导的突触病理才刚刚开始出现，需要进一步研究 调查过了。来自我们实验室的强有力的初步数据暗示了几种突触后丝裂原/Thr激酶(CaMKII， 和一种磷酸酶(钙调神经磷酸酶(CaN))作为导致急性Aβ的关键分子。 诱导LTP中断，可能是通过受损的NMDA受体钙离子内流。目前尚不清楚是否 这些相同的信号机制介导了慢性Aβ诱导的突触抑制和消除，但 这里公布的和初步的数据表明，CAN活动是必需的。重要的是，所有这些 在突触后信号网络中，激酶和磷酸酶相互作用，整合 NMDAR活动，以推广LTP或LTD。事实上，突触锚定的PKA和CaN由支架 蛋白AKAP79/150似乎在促进PKA、CAN、DAPK1和DAPK1之间的信号串扰中起关键作用 CaMKII在突触部位建立正常的LTP/LTD平衡。在这个多PI项目中，我们将测试 假设β通过干扰突触引起急性(目标1和2)和慢性(目标3和4)突触功能障碍 该信令网络及其下游效应器的平衡有利于LTD，导致LTP和 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.