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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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.

项目概要摘要 β淀粉样蛋白诱导的突触功能障碍中的突触后激酶/磷酸酶网络阿尔茨海默病 (AD) 的特点是突触功能受损和关键部位的突触丧失。学习和记忆所需的前脑区域，包括海马体。 AD 的成因仍然存在争议（β 淀粉样蛋白；Aβ 与 tau 蛋白），存在很强的遗传、生化、解剖学和电生理学证据支持 Aβ 足以启动细胞过程，导致严重的例如，亚微摩尔剂量的 Aβ 可急性（几分钟内）长期抑制。增强（LTP），一种对学习和记忆至关重要的突触可塑性，此外，更长的 Aβ。暴露（数天至数周）会导致抑郁并通过a消除兴奋性突触然而，需要 NMDA 受体信号传导的下游信号网络。急性和慢性 Aβ 介导的突触病理学才刚刚开始出现，需要进一步研究我们实验室的有力初步数据表明多种突触后丝氨酸/苏氨酸激酶（CaMKII、 DAPK1、PKA）和磷酸酶（钙调神经磷酸酶 (CaN)）是导致急性 Aβ- 的关键分子参与者可能是通过 NMDA 受体 Ca2+ 进入受损引起的 LTP 破坏，目前尚不清楚是否如此。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，但是此处公布的数据和初步数据表明，CaN 活性是必需的。激酶和磷酸酶在突触后信号网络中相互作用，该网络整合了 NMDAR 活性可促进 LTP 或 LTD。事实上，支架对 PKA 和 CaN 的突触锚定。蛋白 AKAP79/150 似乎对于促进 PKA、CaN、DAPK1 和 CaMKII 在突触位点建立正常的 LTP/LTD 平衡在这个多 PI 项目中，我们将测试假设 Aβ 通过扰乱突触功能而导致急性（目标 1 和 2）和慢性（目标 3 和 4）突触功能障碍。该信号网络及其下游效应器的平衡有利于LTD，导致LTP和突触消除。