Targeting the apoE/ABeta Interaction as a Novel AD Therapy
将 apoE/Aβ 相互作用作为一种新型 AD 疗法
基本信息
- 批准号:8678647
- 负责人:
- 金额:$ 13.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-09-12 至 2015-09-11
- 项目状态:已结题
- 来源:
- 关键词:AbbreviationsAffectAffinityAgonistAllelesAlzheimer&aposs DiseaseAmino Acid SubstitutionAmyloidAmyloid beta-ProteinAmyloid depositionAnimal ModelApolipoprotein EApolipoproteins BApplications GrantsAreaBindingBinding SitesBiologicalBiological AssayBiomedical TechnologyBiomimeticsBlood - brain barrier anatomyBrainCell Culture TechniquesCerebral Amyloid AngiopathyChemicalsChimera organismCircular DichroismClinical ResearchCollaborationsComplementComplexDataDepositionDevelopmentDrug KineticsEffectivenessEquilibriumEventField Flow FractionationGenesGoalsHalf-LifeHemorrhageHumanImageIngestionKnock-outLDL-Receptor Related Protein 1LeadLengthLettersLigandsLipoproteinsMeasurementMediatingMemory impairmentMicroscopyModificationMusNeuronsOralOral AdministrationOutcome MeasurePathogenesisPathologyPatientsPenetrationPeptidesPermeabilityPharmaceutical ChemistryPreventionProtein IsoformsProteinsRadiolabeledResistanceRiskSerumSpectroscopy, Fourier Transform InfraredStructureSurface Plasmon ResonanceTestingTherapeuticTherapeutic AgentsThioflavin TToxic effectTransgenic AnimalsTransgenic MiceTransgenic OrganismsTransmission Electron MicroscopyTreatment EfficacyVaccinationWild Type Mouseapolipoprotein E-3apolipoprotein E-4basebehavior testdesigngel electrophoresisgene replacementimprovedin vitro testingin vivoinhibitor/antagonistintravenous administrationlight scatteringmouse modelnovelnovel therapeutic interventionpeptidomimeticspreventradiotracerreceptorresearch studyresponsereuptakesynthetic peptidetherapeutic developmenttransgenic model of alzheimer diseasetwo-photon
项目摘要
DESCRIPTION (provided by applicant): Our main hypothesis is that a therapeutic agent blocking the interaction between apolipoprotein E and B-amyloid will be effective in reducing and preventing 6-amyloid ( AB ) related pathology of Alzheimer's disease (AD).The B-amyloid ( AB ) cascade hypothesis maintains that accumulation of the AB peptide constitutes a critical event in the early pathogenesis of AD. An excess of AB assembles into toxic oligomers and subsequently into deposits in the brain's parenchyma and in walls of vessels producing cerebral amyloid angiopathy (CAA).The direct binding between AB and apolipoprotein E (apoE) has been identified as an important factor promoting the deposition of AB in the CMS and regulating its clearance across the blood-brain-barrier (BBB).The magnitude of apoE/AB interaction appears to be isoform specific, providing one explanation for the linkage between the apoE4 allele and an increased risk of sporadic AD. We have demonstrated that blocking the apoE/AB binding with a synthetic peptide - AB 12-28P, that mimics the apoE binding site on AB and was modified for in vivo application, reduces the burden of parenchynal AB deposits and CAA, as well as preventing memory impairment in AD transgenic (Tg) mice (Sadowski et al. AJP, 2004; 165:937; Sadowski et al., PNAS, 2006; 103:18787). In contrast, anti- AB vaccination approaches prevent only parenchymal AB deposition without affecting the CAA burden. In addition, vaccination appears to increase the risk of perivascular hemorrhages which were absent in AD Tg animals treated with AB 12-28P. In this grant proposal, we are planning to develop non-toxic peptidomimetic antagonists of the apoE/ AB interaction which will be based on the AB 12-28 sequence. The objectives are to improve therapeutic efficacy, BBB penetration, and biostability. Due to the inherent biomimetic character of peptidomimetics, their resistance to degradation, and ease of chemical modification, this strategy has been successfully employed in the past to develop a number of therapeutically promising compounds. Selected peptidomimetic compounds will be tested in AD Tg models including those expressing differing human apoE isoforms. This will be done to predict the therapeutic response in carriers of the various human apoE isoforms. To determine whether this form of therapy can lead to a reduction of already existing AB deposits we will perform in vivo imaging of AB plaques in AD Tg mice using transcranial two-photon microscopy. Although the primary goal of blocking the apoE/ AB interaction is to prevent AB fibrillar assembly and deposition there are also several other potential benefits of this approach which we investigate in this application. Thus, we will determine the effect of blocking the apoE/ AB interaction on AB and apoE clearance across the BBB, the equilibrium between AB oligomers and fibril formation, and intraneuronal accumulation of apoE/ AB complexes. The overall goal of this proposal is to bring this novel therapeutic approach closer to clinical studies and to identify a lead peptidomimetic compound, which could be further developed for safe, long-term application in humans
描述(由申请人提供):我们的主要假设是阻断载脂蛋白E和B-淀粉样蛋白之间的相互作用的治疗剂将有效减少和预防阿尔茨海默病(AD)的6-淀粉样蛋白(AB)相关病理学。B-淀粉样蛋白(AB)级联假说认为AB肽的积累构成AD早期发病机制中的关键事件。过量的AB在脑实质和血管壁聚集形成毒性寡聚体,沉积形成脑淀粉样血管病(cerebral amyloid angiopathy,CAA)。AB与载脂蛋白E(apolipoprotein E,apoE)的直接结合是促进AB在CMS中沉积和调节其通过血脑屏障(blood-brain-barrier,BBB)的重要因素。apoE/apoE比值的大小与AB在脑淀粉样血管病(cerebral amyloid angiopathy,CAA)中的表达有关。AB相互作用似乎是亚型特异性的,为apoE 4等位基因与散发性AD风险增加之间的联系提供了一种解释。我们已经证明,用合成肽- AB 12- 28 P(其模拟AB上的apoE结合位点并被修饰用于体内应用)阻断apoE/AB结合,降低了实质AB沉积物和CAA的负担,以及预防AD转基因(Tg)小鼠中的记忆损伤(Sadowski等人,AJP,2004; 165:937; Sadowski等人,PNAS,2006; 103:18787)。相反,抗AB疫苗接种方法仅预防实质AB沉积而不影响CAA负荷。此外,疫苗接种似乎增加了血管周围病变的风险,而这在用AB 12- 28 P处理的AD Tg动物中是不存在的。在这项资助计划中,我们计划开发基于AB 12-28序列的apoE/ AB相互作用的无毒拟肽拮抗剂。目的是提高治疗效果、BBB渗透性和生物稳定性。由于肽模拟物固有的仿生特性、它们对降解的抗性和易于化学修饰,这种策略在过去已成功地用于开发许多有治疗前景的化合物。将在AD Tg模型(包括表达不同人apoE同种型的模型)中测试选定的拟肽化合物。这将用于预测各种人apoE同种型携带者的治疗反应。为了确定这种形式的治疗是否可以导致已经存在的AB沉积物的减少,我们将使用经颅双光子显微镜对AD Tg小鼠中的AB斑块进行体内成像。虽然阻断apoE/ AB相互作用的主要目的是防止AB纤维组装和沉积,但我们在本申请中研究的这种方法也有几个其他潜在的好处。因此,我们将确定阻断apoE/ AB相互作用对AB和apoE穿过BBB的清除率、AB寡聚体和原纤维形成之间的平衡以及apoE/ AB复合物的神经元内积累的影响。该提案的总体目标是使这种新的治疗方法更接近临床研究,并确定一种先导肽模拟物化合物,该化合物可以进一步开发用于人类的安全,长期应用
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)
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MARTIN Joseph SADOWSKI其他文献
MARTIN Joseph SADOWSKI的其他文献
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{{ truncateString('MARTIN Joseph SADOWSKI', 18)}}的其他基金
Role of Microglia in Neurodegeneration -Effect of ApoE
小胶质细胞在神经退行性变中的作用 - ApoE 的作用
- 批准号:
10370582 - 财政年份:2022
- 资助金额:
$ 13.5万 - 项目类别:
Role of Microglia in Neurodegeneration -Effect of ApoE
小胶质细胞在神经退行性变中的作用 - ApoE 的作用
- 批准号:
10631864 - 财政年份:2022
- 资助金额:
$ 13.5万 - 项目类别:
Mechanisms of Peroxiredoxin 6 Endowed Protection in Alzheimer’s Disease
过氧化还原蛋白 6 对阿尔茨海默病的保护机制
- 批准号:
9975324 - 财政年份:2020
- 资助金额:
$ 13.5万 - 项目类别:
Mechanisms of Peroxiredoxin 6 Endowed Protection in Alzheimer’s Disease
过氧化还原蛋白 6 对阿尔茨海默病的保护机制
- 批准号:
10343791 - 财政年份:2020
- 资助金额:
$ 13.5万 - 项目类别:
Mechanisms of Peroxiredoxin 6 Endowed Protection in Alzheimer’s Disease
过氧化还原蛋白 6 对阿尔茨海默病的保护机制
- 批准号:
10551833 - 财政年份:2020
- 资助金额:
$ 13.5万 - 项目类别:
Mechanisms of Apolipoprotein E Isoform Conferred Susceptibility and Resistance to Alzheimer's Disease
载脂蛋白 E 同工型赋予阿尔茨海默病易感性和抵抗力的机制
- 批准号:
9312725 - 财政年份:2016
- 资助金额:
$ 13.5万 - 项目类别:
Mechanisms of Apolipoprotein E Isoform Conferred Susceptibility and Resistance to Alzheimer's Disease
载脂蛋白 E 同工型赋予阿尔茨海默病易感性和抵抗力的机制
- 批准号:
9912080 - 财政年份:2016
- 资助金额:
$ 13.5万 - 项目类别:
Mechanisms of Apolipoprotein E Isoform Conferred Susceptibility and Resistance to Alzheimer's Disease
载脂蛋白 E 同工型赋予阿尔茨海默病易感性和抵抗力的机制
- 批准号:
9193845 - 财政年份:2016
- 资助金额:
$ 13.5万 - 项目类别:
Peptoid Antagonists of the ApoE/ABeta Interaction as a Novel Anti-ABeta Therapy.
ApoE/Aβ 相互作用的类肽拮抗剂作为一种新型抗 Aβ 疗法。
- 批准号:
8742110 - 财政年份:2013
- 资助金额:
$ 13.5万 - 项目类别:
Peptoid Antagonists of the ApoE/ABeta Interaction as a Novel Anti-ABeta Therapy
ApoE/Aβ 相互作用的类肽拮抗剂作为新型抗 Aβ 疗法
- 批准号:
8509559 - 财政年份:2009
- 资助金额:
$ 13.5万 - 项目类别:
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