Validating a Novel Lipid Phosphatase Target in Alzheimer's Disease
验证阿尔茨海默氏病的新型脂质磷酸酶靶点
基本信息
- 批准号:8212249
- 负责人:
- 金额:$ 35万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-01-15 至 2015-12-31
- 项目状态:已结题
- 来源:
- 关键词:AMPA ReceptorsAddressAftercareAlzheimer&aposs DiseaseAmyloidAmyloid beta-Protein PrecursorAmyloid depositionAnimal ModelBehavioralBiochemicalBiological ModelsBrainCell surfaceCognition DisordersCrossbreedingCyclic AMP-Responsive DNA-Binding ProteinDataDevelopmentDiseaseDisease ProgressionElementsEnzymesFunctional disorderFutureGenesGeneticGenotypeGoalsHippocampus (Brain)Impaired cognitionImpairmentIn VitroKnockout MiceLeadLearningLinkLipidsLong-Term PotentiationMediator of activation proteinMemoryMemory impairmentMetabolismMolecularMusNeuronal DysfunctionNeuronsNeurophysiology - biologic functionPathogenesisPathway interactionsPatientsPeptidesPhosphatidylinositolsPhospholipidsPhosphoric Monoester HydrolasesPhosphorylationPhosphorylation SitePlayPredispositionPropertyProtein Binding DomainProteinsPublishingRadialResistanceRoleSeriesShort-Term MemorySignal PathwaySignal TransductionSliceSolidStagingSynapsesSynaptic plasticitySystemTestingTg2576TherapeuticTherapeutic AgentsTransgenic MiceWaterWorkarmbasebehavior testconditioned fearin vivoinhibitor/antagonistmouse modelmutantnoveloverexpressionpublic health relevancepupreconstitutionresearch studysmall moleculesynaptojanintherapeutic targettranscription factor
项目摘要
DESCRIPTION (provided by applicant): The amyloid ¿-peptide (A¿), which originates from the proteolytic cleavage of amyloid precursor protein (APP), plays a central role in the pathogenesis of Alzheimer's disease (AD). Mounting evidence indicates that different species of A¿, such as A¿ oligomers and fibrils, may contribute to AD pathogenesis via distinct mechanisms at different stages of the disease. Importantly, elevated levels of A¿ oligomers closely correlate with cognitive decline and disease progression in animal models of AD. At the cellular level, A¿ disrupts synaptic plasticity, including the impairment of long-term potentiation (LTP), an electrophysiological correlate of learning and memory in the mammalian hippocampus. Our recently published work demonstrated that A¿ oligomers caused a decrease in the levels of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], a phospholipid that regulates key aspects of neural function. The destabilizing effect of A¿ on PI(4,5)P2 metabolism was not observed in neurons derived from mice containing higher brain levels of PI(4,5)P2 levels owing to the hemizygous deletion of synaptojanin 1 (Synj1 +/-). Synj1 is the main PI(4,5)P2 phosphatase [PI(4,5)P2 degrading enzyme] in the brain and synapses. Furthermore, the well characterized inhibitory effect of A¿ on LTP was strongly suppressed in brain slices from the Synj1 +/- mice. Furthermore, our preliminary results showed that A¿-induced suppression of phosphorylation of cAMP response element-binding protein (CREB), a critical transcription factor associated with synaptic plasticity and memory, was absent in primary neurons derived from Synj1+/- mice. Thus, based on these results, we hypothesize that inhibition of Synj1 may ameliorate A¿-induced synaptic dysfunction and memory impairment in AD. To this end, the main goals of this proposal are to employ biochemical and mouse genetic approaches to investigate the role of Synj1 in A¿-induced disruption of neuronal signaling and further validate Synj1 as a therapeutic target using cultured neurons and in vivo mouse models of AD. Specifically, we will investigate the role of Synj1 in A¿2-induced alterations in neuronal signaling, and will also determine if hemizygous deletion of Synj1 can ameliorate learning and memory impairments in an animal model of AD. Thus, our study will establish Synj1 as a validated target based on a molecular and system level target characterization study. Successful completion of this work will establish a solid rationale for the development of small molecule inhibitors that could selectively target Synj1, as potential therapeutic agents in AD.
PUBLIC HEALTH RELEVANCE: Alzheimer's disease is characterized clinically by memory impairment and pathologically by the deposition of amyloid-2 peptide (A2) in the brains of AD patients. Evidence is accumulating which supports the hypothesis that A2 may be a factor in early neuronal dysfunction associated with AD. Specifically, levels of A2 correlate with disease progression in animal models of AD. In the brain, A2 interferes with normal neuronal function by mechanisms that are not yet fully understood. We have recently published data indicating that a specific lipid, phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], which regulates key aspects of neural function, is altered after treatment of neurons with A2. Additionally, mice with low levels of a specific lipid phosphatase, synaptojanin 1 (Synj1), responsible for metabolizing PI(4,5)P2, are resistant to A2-induced neuronal dysfunction. We propose to further investigate the role Synj1 in A2-induced neuronal dysfunction by using mutants of Synj1 to probe its function in neurons lacking endogenous Synj1. Additionally, we propose to cross a mouse model of AD with mice lacking one copy of Synj1. Since this genotype was protective in vitro, we expect these mice to have ameliorated AD-associated behavioral deficits in learning and memory tasks. Completion of these studies will determine if Synj1 can be a valid target for future AD therapeutic strategies.
描述(由应用提供):淀粉样淀粉样蛋白(a¿),源自淀粉样蛋白前体蛋白(APP)的蛋白水解切割,在阿尔茨海默氏病(AD)的发病机理中起着核心作用。越来越多的证据表明,不同种类的A检测(例如寡聚物和原纤维)可能会通过疾病的不同阶段的不同机制来促进AD发病机理。重要的是,A的低聚物水平升高与AD动物模型的认知下降和疾病进展密切相关。在细胞水平上,a破坏了合成可塑性,包括长期增强损害(LTP),这是哺乳动物海马中学习和记忆的电生理相关性。我们最近发表的工作表明,A低聚物导致磷脂酰肌醇4,5-双磷酸盐[PI(4,5)P2]的水平降低,这是一种调节神经功能关键方面的磷脂。在含有较高脑部PI的较高脑水平的PI(4,5)P2水平的神经元中,未观察到A检测对Pi(4,5)P2代谢的不稳定作用,这是由于突触素膜1(Synj1 +/-)的半巧合缺失。 Synj1是大脑和突触中的主要PI(4,5)P2磷酸酶[Pi(4,5)P2降解酶。此外,在Synj1 +/-小鼠的大脑切片中,A级对LTP的抑制作用良好。此外,我们的初步结果表明,在synj1 +/-小鼠的原代神经元中不存在A诱导的cAMP反应元素结合蛋白(CREB)的磷酸化磷酸化(CREB),这是与合成可塑性和记忆相关的关键转录因子。基于这些结果,我们假设抑制Synj1可能会改善AD诱导的突触功能障碍和AD的记忆障碍。为此,该提案的主要目标是利用生化和小鼠遗传方法来研究Synj1在A诱导的神经元信号破坏中的作用,并进一步验证Synj1作为使用培养的神经元和AD体内小鼠模型的治疗靶标。具体而言,我们将研究synj1在A诱导的神经元信号变化中的作用,还将确定Synj1的半合整缺失是否可以改善AD动物模型中的学习和记忆障碍。这是,我们的研究将基于分子和系统水平靶标的研究将SYNJ1建立为经过验证的靶标。这项工作的成功完成将建立一个扎实的基本原理,以开发可以选择性靶向Synj1的小分子抑制剂,作为AD中的潜在治疗剂。
公共卫生相关性:阿尔茨海默氏病在临床上以记忆障碍为特征,并在病理上以淀粉样蛋白2肽(A2)在AD患者的大脑中的沉积。证据正在积累,这支持A2可能是与AD相关的早期神经元功能障碍的一个因素。具体而言,A2的水平与AD动物模型中的疾病进展相关。在大脑中,A2通过尚未完全理解的机制干扰正常的神经元功能。我们最近发布了数据表明,调节神经元关键方面的特定脂质磷脂酰肌醇4,5-双磷酸[PI(4,5)P2]在用A2治疗神经元后会改变。另外,负责代谢Pi(4,5)P2的特定脂质磷酸酶(Synj1)的小鼠抗A2诱导的神经元功能障碍具有抗性。我们建议通过使用synj1的突变体来探测其在缺乏内源性synj1的神经元中的功能,以进一步研究synj1在A2诱导的神经元功能障碍中的作用。此外,我们建议将AD的小鼠模型与缺少一份Synj1副本的小鼠穿越。由于该基因型在体外受到保护,因此我们期望这些小鼠在学习和记忆任务中可以改善与AD相关的行为缺陷。这些研究的完成将确定Synj1是否可以成为未来AD疗法策略的有效目标。
项目成果
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