Targeting Endosomal dysfunction as a new source of biomarkers for Alzheimer's disease
将内体功能障碍作为阿尔茨海默病生物标志物的新来源
基本信息
- 批准号:10588259
- 负责人:
- 金额:$ 51.05万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-03-15 至 2026-12-31
- 项目状态:未结题
- 来源:
- 关键词:APLP1 geneAccelerationAddressAffectAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease pathologyAlzheimer&aposs disease patientAlzheimer&aposs disease riskAlzheimer’s disease biomarkerAmyloid beta-ProteinAmyloid beta-Protein PrecursorBiologicalBiological AssayBiological MarkersBrainCell Adhesion MoleculesCellsCellular biologyCerebrospinal FluidCognitiveConfocal MicroscopyConsensusCore ProteinCytopathologyDataDefectDevelopmentDiagnosticDiseaseDisease ProgressionElectron MicroscopyEndosomesEnzyme-Linked Immunosorbent AssayExtracellular SpaceFrontotemporal DementiaFunctional disorderGenesGeneticGoalsHistopathologyHumanImageKnock-outKnockout MiceLewy Body DiseaseLinkLiquid ChromatographyMeasuresModelingMusMutant Strains MiceMutationNerve DegenerationNeurodegenerative DisordersNeurofibrillary TanglesNeuronsParkinson DiseaseParticipantPathogenicityPathologyPathway interactionsPatientsPeripheralPlasmaPreparationProteinsProteomicsSamplingSenile PlaquesSourceSpecificityTechnologyTestingTherapeutic InterventionTransgenic MiceWestern Blottingamyloid pathologybeta secretasebeta-site APP cleaving enzyme 1biomarker discoverybiomarker identificationbiomarker panelde novo mutationdesigndrug discoveryexosomegenetic risk factorhuman pluripotent stem cellmouse modelmutantnervous system disorderpotential biomarkerprodromal Alzheimer&aposs diseaseprotein expressionrare variantreceptorspecific biomarkerstandem mass spectrometrytau Proteinstrafficking
项目摘要
Endosomal dysfunction is a well-accepted cell biological feature in Alzheimer’s disease (AD). However,
biomarkers reflecting endosomal traffic defects are still lacking. Current imaging and cerebrospinal fluid (CSF)
AD biomarkers focus primarily on the histopathology of the disease—that is, biomarkers that are linked to
neurofibrillary tangles and amyloid plaques. This proposal is designed to expand this focus to develop
biomarkers of the ‘cell biology’ of AD. Such biomarkers could potentially accelerate drug discovery, as
therapeutic interventions are currently being developed that target endosomal trafficking defects in AD.
Genetic and cell biology studies have previously linked the endosomal trafficking assembly Retromer to
AD pathology. Most notable are deficiencies and rare mutations in retromer’s core protein, VPS35, and
retromer’s receptor, SORL1. Depletion of either VPS35 or SORL1 mimics the core cytopathology in AD, enlarged
endosomes in neurons, with concomitant mis-trafficking of endosomal cargoes.
In an effort to characterize defects in the endocytic pathway resulting from retromer dysfunction, we recently
completed a proteomic screen of CSF of VPS35 knock-out (KO) mice and control littermates. Among the proteins found elevated in the CSF of VPS35 KO mice were well established β-secretase BACE1 substrates, includingAPP (Amyloid Precursor Protein); APLP1/2 (Amyloid Beta Precursor Like Proteins 1 and 2); and CHL1 (Neuralcell adhesion molecule L1-like protein). Two of these proteins --APLP1 and CHL1-- were further validated inmouse CSF, and human CSF from cognitively healthy participants and prodromal AD patients. Collectively, our studies suggest BACE1 substrates as potential biomarkers of retromer-dependent endosomal dysfunction.
However, since VPS35 is implicated in other neurodegenerative disorders, including Parkinson’s disease (PD),
these new biomarkers may not be specific to AD. Therefore, relying on these exciting findings, but moving
towards the development of a panel of biomarkers reflecting endosomal trafficking defects that are specific to
AD, we will examine SORL1 mouse models and human pluripotent stem cell (hPSC) SORL1-derived neurons
as a new source of biomarkers of endosomal trafficking. We will also investigate exosomes as an additional
source of biomarkers of endosomal defects. Lastly, since Sorl1 protein levels are altered in AD and CSF from
AD patients, we will examine SORL1 CSF levels as a potential biomarker for AD. Completion of this study will
provide evidence that SORL1-dependent endosomal trafficking is a new source of biomarkers for AD.
Moreover, we predict that the extensive studies here proposed will identify a unique and specific
endosomal biomarker of the “cell biology” of AD.
内体功能障碍是阿尔茨海默病(AD)的一个公认的细胞生物学特征。然而,
项目成果
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Sabrina Alves Simoes Spassov其他文献
Sabrina Alves Simoes Spassov的其他文献
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{{ truncateString('Sabrina Alves Simoes Spassov', 18)}}的其他基金
Investigate the utility of APLP1 as an endosomal biomarker for Alzheimer's Disease in Down Syndrome
研究 APLP1 作为唐氏综合症阿尔茨海默氏病内体生物标志物的效用
- 批准号:
10727134 - 财政年份:2023
- 资助金额:
$ 51.05万 - 项目类别:
Targeting Endosomal dysfunction as a new source of biomarkers for Alzheimer's disease
将内体功能障碍作为阿尔茨海默病生物标志物的新来源
- 批准号:
10367484 - 财政年份:2022
- 资助金额:
$ 51.05万 - 项目类别:
Endosomal dysfunction, a new source of biomarkers for Alzheimer's disease.
内体功能障碍,阿尔茨海默病生物标志物的新来源。
- 批准号:
10303621 - 财政年份:2021
- 资助金额:
$ 51.05万 - 项目类别:
Endosomal dysfunction, a new source of biomarkers for Alzheimer's disease.
内体功能障碍,阿尔茨海默病生物标志物的新来源。
- 批准号:
10471930 - 财政年份:2021
- 资助金额:
$ 51.05万 - 项目类别:
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