A-beta/APP signaling impairs CaMKII-dependent synaptic plasticity after ischemic brain injury
A-beta/APP 信号传导损害缺血性脑损伤后 CaMKII 依赖性突触可塑性
基本信息
- 批准号:10312704
- 负责人:
- 金额:$ 4.02万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-05-01 至 2021-10-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAlzheimer&aposs DiseaseAlzheimer&aposs disease pathologyAmyloid beta-ProteinAmyloid beta-Protein PrecursorBindingBiochemistryBrain DiseasesCa(2+)-Calmodulin Dependent Protein KinaseCardiopulmonary ResuscitationCause of DeathCell DeathCellsCerebral IschemiaChemicalsChronicCleaved cellClinical ResearchCognitive deficitsConfocal MicroscopyDLG4 geneDrug TargetingElectrophysiology (science)Excitatory SynapseHeart ArrestHippocampus (Brain)HourHumanImageImpaired cognitionImpairmentInhibitory SynapseIntrabodyIschemiaIschemic Brain InjuryKnock-outKnockout MiceLabelLeadLearningLong-Term PotentiationMeasuresMediatingMediator of activation proteinMemoryMemory impairmentModelingMonitorMusN-MethylaspartateNeuronsPathologicPathologyPathway interactionsPhysiologicalProtein PrecursorsProteinsProteolysisPublishingResearchResistanceResuscitationRisk FactorsRoleSignal PathwaySignal TransductionSignaling ProteinSliceSynapsesSynaptic plasticityTechniquesTestingTherapeuticTimeWild Type MouseWorkcalmodulin-dependent protein kinase IIdesigneffective therapyexcitotoxicityexperimental studygephyrinimprovedin vivo Modelinhibitor/antagonistinsightlong term memorynervous system disorderneuron lossoAβpreventprotein expressionreceptorrecruit
项目摘要
Project Summary
Long-term potentiation (LTP) and other forms of synaptic plasticity are cellular correlates of learning and
memory. The Ca2+/CaM-dependent protein kinase II (CaMKII) facilitates LTP by translocating to stimulated
synapses and phosphorylating local targets. LTP is impaired in global cerebral ischemia (GCI) and Alzheimer’s
disease (AD), two neurological disorders that demand effective treatment. GCI has acute and chronic effects:
initially, it triggers excitotoxic neuronal cell death; long-term, it impairs LTP within the surviving neurons.
Together, the neuronal loss and compromised synaptic plasticity underlie cognitive decline observed after
ischemia, and an ideal therapy would target both. My proposed research aims to determine whether GCI-induced
LTP impairments utilize signaling pathways previously implicated in AD.
The amyloid-β precursor protein (APP) is proteolytically cleaved to form amyloid-β peptide1-42 (Aβ).
Exogenous application of Aβ impairs LTP and CaMKII synaptic enrichment in hippocampal neurons. How does
Aβ signal to disrupt CaMKII? Recent published work suggests that APP acts not only upstream of Aβ (as the Aβ
precursor) but also downstream (as the Aβ receptor): Aβ association with APP was found to be required for LTP
and memory impairments, as APP knockout (KO) prevented exogenous Aβ-induced deficits. While increased
APP and Aβ are well-studied in AD pathology, a potential function for Aβ/APP signaling in ischemia has not been
fully elucidated. Studies from our lab indicate that GCI- and Aβ-induced reductions in LTP utilize a common
mechanism through CaMKII. To test the hypothesis that APP mediates the GCI-induced LTP impairment by
disrupting CaMKII signaling, I will test three specific aims: i) whether APP mediates Aβ-induced impairments in
LTP and CaMKII synaptic translocation, ii) APP mediates GCI-induced LTP impairments, and iii) whether the
therapeutic window for protecting synaptic plasticity after GCI shows an extended range (days), even if the
window for protecting neuronal cell death is much shorter (hours). This project will utilize acute hippocampal
slices and cultures hippocampal neurons for biochemistry, slice electrophysiology, and live confocal microscopy.
Imaging will employ FingR intrabodies that are designed to label endogenous proteins, including CaMKIIα and
post-synaptic markers. The mouse in vivo model of global cerebral ischemia (GCI) closely mimics the most
prevalent human condition (cardiac arrest). These optimized approaches will allow me to investigate whether
potential cross-talk between APP/Aβ and CaMKII underlies impaired LTP following ischemic brain injury. Results
from this project will improve our understanding of neurological disorders that utilize Aβ/APP-dependent
mechanisms to impair synaptic plasticity.
项目摘要
长时程增强(LTP)和其他形式的突触可塑性是学习和记忆的细胞相关物
记忆Ca 2 +/CaM依赖性蛋白激酶II(CaMKII)通过转运到刺激的LTP来促进LTP。
突触和磷酸化局部目标。LTP在全脑缺血(GCI)和阿尔茨海默病中受损
AD是两种需要有效治疗的神经系统疾病。GCI具有急性和慢性影响:
最初,它触发兴奋毒性神经元细胞死亡;长期,它损害存活神经元内的LTP。
总之,神经元损失和受损的突触可塑性是在注射后观察到的认知下降的基础。
理想的治疗方法是针对这两种疾病。我提出的研究旨在确定GCI诱导的
LTP损伤利用先前与AD有关的信号通路。
淀粉样β前体蛋白(APP)被蛋白水解裂解形成淀粉样β肽1 -42(Aβ)。
外源性Aβ损伤海马神经元LTP和CaMK Ⅱ突触富集如何
Aβ信号破坏CaMKII?最近发表的研究表明,APP不仅作用于Aβ的上游(如Aβ
前体)以及下游(作为Aβ受体):发现Aβ与APP的结合是LTP所需的
和记忆障碍,因为APP敲除(KO)阻止了外源性Aβ诱导的缺陷。虽然增加了
APP和Aβ在AD病理学中得到了充分的研究,但Aβ/APP信号在缺血中的潜在功能还没有得到充分的研究。
充分阐明。我们实验室的研究表明,GCI和Aβ诱导的LTP降低利用了一个共同的机制,
通过CaMKII机制。为了验证APP介导GCI诱导的LTP损伤的假设,
干扰CaMKII信号传导,我将测试三个特定的目标:i)APP是否介导Aβ诱导的损伤,
LTP和CaMK II突触易位,ii)APP介导GCI诱导的LTP损伤,以及iii)
GCI后保护突触可塑性的治疗窗口显示出延长的范围(天),即使
保护神经元细胞死亡的时间窗短得多(小时)。本项目将利用急性海马
切片和培养海马神经元用于生物化学、切片电生理学和活体共聚焦显微镜。
成像将采用FingR胞内抗体,其设计用于标记内源性蛋白质,包括CaMKIIα和
突触后标记小鼠全脑缺血(GCI)的体内模型非常接近于模拟大多数
普遍的人类状况(心脏骤停)。这些优化的方法将使我能够调查是否
APP/Aβ和CaMK Ⅱ之间的潜在相互作用是缺血性脑损伤后LTP受损的基础。结果
从这个项目将提高我们对利用Aβ/APP依赖的神经系统疾病的理解,
损害突触可塑性的机制。
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)
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Olivia Ruth Asfaha其他文献
Olivia Ruth Asfaha的其他文献
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{{ truncateString('Olivia Ruth Asfaha', 18)}}的其他基金
Comparative testing of tatCN19o for neuroprotection in rodent tMCAo
tatCN19o 对啮齿动物 tMCAo 神经保护作用的比较测试
- 批准号:
10671969 - 财政年份:2023
- 资助金额:
$ 4.02万 - 项目类别:
MRP4 extrudes cAMP for localized regulation of calcium channel activity
MRP4 挤出 cAMP 来局部调节钙通道活性
- 批准号:
8774113 - 财政年份:2013
- 资助金额:
$ 4.02万 - 项目类别:
MRP4 extrudes cAMP for localized regulation of calcium channel activity
MRP4 挤出 cAMP 来局部调节钙通道活性
- 批准号:
8649990 - 财政年份:2013
- 资助金额:
$ 4.02万 - 项目类别: