Identification of novel APP-specific alpha secretase in human umbilical cord blood sera
人脐带血血清中新型 APP 特异性 α 分泌酶的鉴定
基本信息
- 批准号:9380529
- 负责人:
- 金额:$ 22.43万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-07-15 至 2019-05-31
- 项目状态:已结题
- 来源:
- 关键词:Abeta synthesisAgeAlpha CellAlzheimer&aposs DiseaseAmyloidAmyloid beta-ProteinAmyloid beta-Protein PrecursorAntibodiesBrainCell-Free SystemCerebrumChinese Hamster Ovary CellCleaved cellComplexCuesCytokine ActivationDementiaDepositionDevelopmentDiagnosisDiseaseDisintegrinsDoseElderlyEnzymesExclusionFamily memberFrequenciesGoalsHumanHuman Amyloid Precursor ProteinImpaired cognitionImpairmentIndividualInflammatoryInfusion proceduresInjection of therapeutic agentInterleukin-1 betaInterleukin-6Ion-Exchange Chromatography ProcedureLengthLigationLinkMediatingMembraneMetalloproteasesMusNeurocognitionNeuronsPathogenesisPathologyPathway interactionsPeptidesPhagocytosisPhosphorylationPreparationPrevalenceProcessProductionProteolysisRecombinantsReportingSerumT-LymphocyteTNF geneTNFRSF5 geneTNFSF5 geneTherapeuticUmbilical Cord BloodUmbilical cord structureWorkZincagedalpha secretasebehavior testbehavioral impairmentbeta secretasebeta-site APP cleaving enzyme 1chemokinecognitive testingconditioned fearcytokineimprovedintraperitonealmonocyteneurogenesisneuron lossneuroprotectionnovelprophylacticrestorationsecretasetau Proteinstreatment strategytumor progressiontumorigenesis
项目摘要
Project Abstract
We have recently shown that sAPPα directly inhibits β-secretase (BACE1) proteolysis of APP, thereby
reducing Aβ production. In addition, our most recent studies show that sAPPα reduces Alzheimer’s disease
(AD)-related tau-hyper-phosphorylation by inhibition of GSK3β. Moreover, while multiple low dose infusions of
human umbilical cord blood-derived monocytes (CB-M) reduce AD pathology and behavioral impairment in
PSAPP mice, in part via phagocytosis of Aβ, aged monocytes show impaired Aβ phagocytosis, which can be
reversed by sAPPα. These results suggest that CB-M have their own α-secretase or activate endogenous α-
secretase in the PSAPP mice. Thus, restoration of sAPPα levels in the brain by shifting the amyloidogenic
towards the non-amyloidogenic (α-secretase) pathway could ameliorate AD-related amyloid and tau pathology,
neuronal loss and cognitive impairment. An increase in α-secretase activity, therefore, is an attractive strategy
for treatment of AD. Several years after descriptive reports on α-secretase, the responsible enzymes have
been identified as members of the family of A Disintegrin And Metalloproteinase (ADAM). Three of these
membrane-anchored zinc-dependent metalloproteinases, ADAM10, ADAM17 and ADAM9, possess α-
secretase activity. However, during the past years, numerous other substrates have been linked to all three
sheddases, some of which could promote AD pathogenesis via activation of cytokines or chemokines. Indeed
ADAM17 is also known as the TNFα converting enzyme (TACE), which releases TNFα, a proinflammatory
cytokine. It has also been reported that CD40L is released from T-cells via ADAM10 and 17 upon CD40
ligation. Furthermore, ADAM10 and ADAM17 are not APP-specific, cleave various substrates and have been
associated with tumorigenesis and tumor progression.
We have most recently found that human umbilical cord blood serum (CBS) markedly enhance APP α-
cleavage and thereby increase sAPPα production in CHO cells expressing wild-type human APP. In addition,
CBS selectively mediated the α-secretase cleavage of neuron-specific, human recombinant full-length APP695
(fAPP695) in a cell-free system, independent from TACE and ADAM10. We partially purified this α-secretase
using DEAE, preparative-grade size exclusion and further ion-exchange chromatography and the present
purified fraction (αCBS Frac.) dose-dependently cleaves fAPP695, also independent from TACE and ADAM10.
Importantly, αCBS Frac. does not cleave precursor pro-inflammatory cytokines, including IL-6 and TNFα.
Furthermore, treatment of 3XTg-AD mice with αCBS Frac by i.c.v. injection markedly increases cerebral
sAPPα levels together with significant decreases in cerebral Aβ production and abnormal tauThr231
phosphorylation. The ultimate goal of this proposal will be to further characterize the effects of αCBS Frac on
AD pathology and behavioral impairment in 3XTg-AD mice, which display both Aβ and tau pathology, and
ultimately identify and characterize this novel and APP specific α-secretase.
项目摘要
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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Jun Tan其他文献
Jun Tan的其他文献
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{{ truncateString('Jun Tan', 18)}}的其他基金
A flavonoid gamma-secretase modulator (GSM) reduces beta-amyloid and tau pathologies in the AD mice
类黄酮 γ 分泌酶调节剂 (GSM) 可减少 AD 小鼠的 β-淀粉样蛋白和 tau 蛋白病理
- 批准号:
9127058 - 财政年份:2015
- 资助金额:
$ 22.43万 - 项目类别:
A flavonoid gamma-secretase modulator (GSM) reduces beta-amyloid and tau pathologies in the AD mice
类黄酮 γ 分泌酶调节剂 (GSM) 可减少 AD 小鼠的 β-淀粉样蛋白和 tau 蛋白病理
- 批准号:
8976888 - 财政年份:2015
- 资助金额:
$ 22.43万 - 项目类别:
Flavonoid-diosmin modulation of Abeta and tau pathologies through GSK-3 signaling
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8627446 - 财政年份:2014
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没食子酸辛酯 (OG) 和促进 APP 的非淀粉样蛋白加工
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$ 22.43万 - 项目类别:
Octyl gallate (OG) and Promotion of non-amyloidogenic processing of APP
没食子酸辛酯 (OG) 和促进 APP 的非淀粉样蛋白加工
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IL-6-mediated Jak2/Stat3 signaling and Brain Development
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