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:10207804
- 负责人:
- 金额:$ 58.32万
- 依托单位:
- 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 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:A kinase anchoring proteinAcuteAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAmyloid beta-ProteinAmyloid beta-Protein PrecursorAnatomyAreaBehavioralBiochemicalBrainCalcineurinCell Surface ReceptorsCell physiologyChronicCyclic AMP-Dependent Protein KinasesDataDementiaDendritic SpinesDoseElectrophysiology (science)EnzymesEquilibriumExcisionExcitatory SynapseFunctional disorderGeneticGenetically Engineered MouseHippocampus (Brain)Impaired cognitionImpairmentLearningLightLong-Term PotentiationMeasuresMediatingMediator of activation proteinMemoryMental DepressionModelingMolecularMusMutateN-Methyl-D-Aspartate ReceptorsNeuronal DysfunctionPathologicPathologyPharmacologyPhosphoric Monoester HydrolasesPhosphorylationPhosphotransferasesProcessProsencephalonProtein FragmentProteinsPublishingReceptor SignalingRegulationResearchRoleScaffolding ProteinSignal PathwaySignal TransductionSiteSurfaceSynapsesSynaptic ReceptorsSynaptic plasticityTestingcalmodulin-dependent protein kinase IIcognitive functiongenetic approachin vivoinnovationmouse modelnew therapeutic targetnovelpostsynapticpreventsynaptic depressionsynaptic functiontargeted treatmenttau 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。虽然病理剂
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
突触病理学。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形式。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
需要 NMDA 受体信号传导的过程。然而,驱动下游信号网络
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
调查了。我们实验室提供的强有力的初步数据表明,几种突触后丝氨酸/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
诱导 LTP 破坏,可能是通过 NMDA 受体 Ca2+ 进入受损。目前尚不清楚是否
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,但是
此处公布的数据和初步数据表明需要 CaN 活性。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,该网络整合了
NMDAR 活动旨在促进 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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
K. Ulrich Bayer其他文献
K. Ulrich Bayer的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('K. Ulrich Bayer', 18)}}的其他基金
CaMKII in global cerebral ischemia: mechanisms and therapeutic intervention
CaMKII 在全脑缺血中的作用:机制和治疗干预
- 批准号:
10531925 - 财政年份:2021
- 资助金额:
$ 58.32万 - 项目类别:
CaMKII in global cerebral ischemia: mechanisms and therapeutic intervention
CaMKII 在全脑缺血中的作用:机制和治疗干预
- 批准号:
10328983 - 财政年份:2021
- 资助金额:
$ 58.32万 - 项目类别:
CaMKII nitrosylation in the age-related decline of synaptic plasticity
CaMKII 亚硝基化在与年龄相关的突触可塑性下降中的作用
- 批准号:
10454912 - 财政年份:2020
- 资助金额:
$ 58.32万 - 项目类别:
CaMKII nitrosylation in the age-related decline of synaptic plasticity
CaMKII 亚硝基化在与年龄相关的突触可塑性下降中的作用
- 批准号:
10222559 - 财政年份:2020
- 资助金额:
$ 58.32万 - 项目类别:
CaMKII nitrosylation in the age-related decline of synaptic plasticity
CaMKII 亚硝基化在与年龄相关的突触可塑性下降中的作用
- 批准号:
10671685 - 财政年份:2020
- 资助金额:
$ 58.32万 - 项目类别:
CaMKII nitrosylation in the age-related decline of synaptic plasticity
CaMKII 亚硝基化在与年龄相关的突触可塑性下降中的作用
- 批准号:
10444721 - 财政年份:2020
- 资助金额:
$ 58.32万 - 项目类别:
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 - 财政年份:2018
- 资助金额:
$ 58.32万 - 项目类别:
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:
9791023 - 财政年份:2018
- 资助金额:
$ 58.32万 - 项目类别:
Restoring synaptic function in Down Syndrome mice
恢复唐氏综合症小鼠的突触功能
- 批准号:
9340289 - 财政年份:2016
- 资助金额:
$ 58.32万 - 项目类别:
Restoring synaptic function in Down Syndrome mice
恢复唐氏综合症小鼠的突触功能
- 批准号:
9243583 - 财政年份:2016
- 资助金额:
$ 58.32万 - 项目类别:
相似海外基金
The Association Between Aging, Inflammation, and Clinical Outcomes in Acute Respiratory Distress Syndrome
衰老、炎症与急性呼吸窘迫综合征临床结果之间的关联
- 批准号:
10722669 - 财政年份:2023
- 资助金额:
$ 58.32万 - 项目类别:
Aging trajectories and outcomes of older adults with acute myeloid leukemia
患有急性髓性白血病的老年人的衰老轨迹和结果
- 批准号:
10735257 - 财政年份:2023
- 资助金额:
$ 58.32万 - 项目类别:
Centella asiatica effects on neuroinflammatory responses in Drosophila models of acute inflammation and aging
积雪草对果蝇急性炎症和衰老模型神经炎症反应的影响
- 批准号:
10415346 - 财政年份:2022
- 资助金额:
$ 58.32万 - 项目类别:
Deciphering the impact of aging and inflammation on neurocognitive impairments in people with Post-Acute Sequelae of COVID-19 (PASC)
解读衰老和炎症对患有 COVID-19 急性后遗症 (PASC) 患者神经认知障碍的影响
- 批准号:
460356 - 财政年份:2021
- 资助金额:
$ 58.32万 - 项目类别:
Operating Grants
Effects of Acute Exercise on Functional Magnetic Resonance Spectroscopy Measures of GABA in Aging and Chronic Stroke
急性运动对衰老和慢性中风中 GABA 功能磁共振波谱测量的影响
- 批准号:
10311114 - 财政年份:2021
- 资助金额:
$ 58.32万 - 项目类别:
Acute exercise and the cerebral metabolic response in aging and Alzheimer's Disease
急性运动与衰老和阿尔茨海默病中的大脑代谢反应
- 批准号:
9886905 - 财政年份:2020
- 资助金额:
$ 58.32万 - 项目类别:
Acute exercise and the cerebral metabolic response in aging and Alzheimer's Disease
急性运动与衰老和阿尔茨海默病中的大脑代谢反应
- 批准号:
10551300 - 财政年份:2020
- 资助金额:
$ 58.32万 - 项目类别:
miRNA Mechanism of Acute Kidney Injury in Aging
衰老过程中急性肾损伤的 miRNA 机制
- 批准号:
9752532 - 财政年份:2018
- 资助金额:
$ 58.32万 - 项目类别:
miRNA Mechanism of Acute Kidney Injury in Aging
衰老过程中急性肾损伤的 miRNA 机制
- 批准号:
9947747 - 财政年份:2018
- 资助金额:
$ 58.32万 - 项目类别:
Sedentary Behaviour Interrupted: Acute, medium and long-term effects on biomarkers of healthy aging, physical function and mortality
久坐行为中断:对健康老龄化、身体功能和死亡率的生物标志物的急性、中期和长期影响
- 批准号:
9278020 - 财政年份:2017
- 资助金额:
$ 58.32万 - 项目类别: