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

β淀粉样蛋白诱导的突触功能障碍中的突触后激酶/磷酸酶网络

• 批准号: 10450777
• 负责人: K. Ulrich Bayer
• 金额: $ 58.32万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10450777
• 关键词: A kinase anchoring protein; Acute; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Anatomy; Area; Behavioral; Biochemical; Brain; Calcineurin; Cell Surface Receptors; Cell physiology; Chronic; Cyclic AMP-Dependent Protein Kinases; Data; Dementia; Dendritic Spines; Dose; Electrophysiology (science); Enzymes; Equilibrium; Excision; Excitatory Synapse; Functional disorder; Genetic; Genetically Engineered Mouse; Hippocampus (Brain); Impaired cognition; Impairment; Learning; Light; Long-Term Potentiation; Measures; Mediating; Mediator of activation protein; Memory; Mental Depression; Modeling; Molecular; Mus; Mutate; N-Methyl-D-Aspartate Receptors; Neuronal Dysfunction; Pathologic; Pathology; Pharmacology; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Process; Prosencephalon; Protein Fragment; Proteins; Publishing; Receptor Signaling; Regulation; Research; Role; Scaffolding Protein; Signal Pathway; Signal Transduction; Site; Surface; Synapses; Synaptic Receptors; Synaptic plasticity; Testing; calmodulin-dependent protein kinase II; cognitive function; genetic approach; in vivo; innovation; mouse model; new therapeutic target; novel; postsynaptic; prevent; synaptic depression; synaptic function; targeted treatment; tau Proteins

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.

项目摘要摘要 淀粉样β诱导的突触功能障碍中的突触后激酶/磷酸酶网络 阿尔茨海默氏病（AD）的特征是突触功能受损和钥匙突触丧失 学习和记忆所需的前脑区域，包括海马。而病理因素 原因AD仍然有争议（淀粉样蛋白β；Aβ与Tau）有强大的遗传，生化，解剖学和 电生理证据支持Aβ足以启动导致严重的细胞过程 突触病理。例如，亚微摩尔剂量的Aβ急性（几分钟之内）抑制长期 增强（LTP），一种突触可塑性，对学习和记忆至关重要。另外，较长的Aβ 暴露（数天到几周）导致抑郁和消除兴奋性突触 需要NMDA接收器信号传导的过程。但是，驱动的下游信号网络 急性和慢性Aβ介导的突触病变才刚刚开始出现，需要进一步 调查。来自我们实验室的强大初步数据暗示了几个突触后Ser/Thr激酶（CAMKII，CAMKII， DAPK1，PKA）和磷酸酶（钙调蛋白（CAN））是负责急性Aβ-的关键分子参与者 通过NMDA接收器CA2+进入可能受损的LTP破坏。尚不清楚是否 这些相同的信号机制介导了慢性Aβ诱导的突触抑制和进化，但 此处介绍的已发布和初步数据表明需要活动。重要的是，所有这些 激酶和磷酸酶在集成的突触后信号网络中相互作用 NMDAR活动以促进LTP或LTD。确实，PKA的突触锚定，可以通过脚手架 蛋白AKAP79/150似乎对于促进PKA，CAN，DAPK1和 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Aβ会引起急性（目标1和2）和慢性（目标3和4）突触功能障碍，通过扰动 该信号网络的平衡及其下游效应以偏爱LTD，从而导致LTP和 消除突触。