Role of APOE in endosomal processing of alpha-synuclein
APOE 在 α-突触核蛋白内体加工中的作用
基本信息
- 批准号:10739682
- 负责人:
- 金额:$ 165.84万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-01 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAffectAllelesAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease patientAlzheimer&aposs disease related dementiaAlzheimer&aposs disease riskApolipoprotein EAstrocytesAutopsyBehavior assessmentBindingBiologicalBiological AssayBody CompositionBrainBrain regionCandidate Disease GeneCell ExtractsCell surfaceCellsCessation of lifeClinicalComplexConditioned Culture MediaCost aspectsCultured CellsDataDementiaDementia with Lewy BodiesDiseaseE proteinEndosomesExhibitsExtracellular ProteinFlow CytometryGene ExpressionGene Expression ProfileGenesGeneticGenetic studyGenotypeGoalsHeparan Sulfate ProteoglycanHumanImpaired cognitionImpairmentIndividualInflammationInflammatoryIntercellular FluidKnock-in MouseKnock-outKnowledgeLewy BodiesLewy Body DiseaseLewy body pathologyLinkLipoprotein ReceptorMeasuresMediatingMicrogliaMicroscopyMolecularMorbidity - disease rateMusNerve DegenerationNeurodegenerative DisordersNeurofibrillary TanglesNeurogliaNeuronsParkinson DiseaseParkinson&aposs DementiaPathogenesisPathologicPathologyPathway interactionsPatientsPatternPhagocytosisPhysiologicalProcessProteinsPsychosesReportingRiskRoleSenile PlaquesStructureSymptomsSystemTREM2 geneTestingTissue-Specific Gene ExpressionVariantalpha synucleinapolipoprotein E-3apolipoprotein E-4brain cellbrain dysfunctionbrain tissuecandidate validationcell typedementia riskexperimental studygenetic risk factorgenetic variantglial activationin vivomouse modelnew therapeutic targetnovelparticlepleiotropismpreventreceptorrisk variantsocietal costssynucleinopathytraffickingtranscriptome sequencinguptake
项目摘要
Role of APOE in endosomal processing of alpha-synuclein
Dementia is among the most harmful and costly aspects of Lewy body disease (LBD) which is comprised of
Parkinson disease (PD) and dementia with Lewy bodies (DLB) and shares some clinical features with
Alzheimer’s disease. In particular, dementia and psychosis are often early and aggressive symptoms in
patients with DLB. Pathologically, these illnesses share the feature of aggregation of misfolded forms of the
protein alpha-synuclein (aSyn), termed Lewy bodies, which spread throughout multiple brain regions during
the disease and are toxic to cells. In addition to Lewy bodies, patients with LBD often have amyloid plaques
and neurofibrillary tangles which are hallmarks of Alzheimer’s disease, and patients with Alzheimer’s disease
often have Lewy bodies in addition to plaques and tangles. The exact mechanism of how aSyn becomes
misfolded and why cognitive decline is accelerated in DLB is unclear. Genetic studies point to a strong link
between increased DLB risk and the APOE4 variant of the gene that encodes apolipoprotein E, another protein
that is also central to Alzheimer’s disease risk. We reported that mice expressing the APOE4 version of the
human APOE gene had accelerated aSyn aggregation and early death compared to other APOE genotypes.
This finding is similar to the effects observed when human APOE genotypes are expressed in mouse models
of Alzheimer’s disease. Our preliminary data indicate that astrocytes and microglia take up aSyn aggregates
and process them through the endolysosomal pathway, which may serve as a compensatory mechanism to
degrade harmful aSyn aggregates. We propose to examine the cell biological transit of aSyn aggregates
through the endolysosomal pathway in astrocytes and microglia and determine if there are differences in this
trafficking related to APOE genotype. We hypothesize that the APOE4 genotype impairs endolysosomal
degradation of aSyn aggregates in both astrocytes and microglia, and that astrocyte expression of APOE4 in
particular drives accelerated aSyn pathology leading to brain dysfunction and neurodegeneration. We will test
whether this effect occurs mainly due to cell-autonomous changes within astrocytes or microglia themselves,
including related to changes in gene expression in those cells, or whether it is mediated through secreted
apolipoprotein E protein particles that are known to have effects by binding to receptors on both neurons and
glia. The main goal of these experiments is to clarify how APOE genotype regulates endolysosomal processing
of aSyn in astrocytes and microglia and how this knowledge can be leveraged to develop novel treatments for
DLB, Alzheimer’s disease, and other related dementias.
APOE在α-突触核蛋白内体加工中的作用
痴呆症是路易体病(LBD)中最有害和最昂贵的方面之一,
帕金森病(PD)和路易体痴呆(DLB),并与帕金森病(PD)和路易体痴呆(DLB)共享一些临床特征。
老年痴呆症特别是,痴呆症和精神病往往是早期和积极的症状,
DLB患者从病理学上讲,这些疾病的共同特点是聚集了错误折叠的形式,
蛋白质α-突触核蛋白(aSyn),称为路易体,它分布在多个大脑区域,
对细胞有毒性。除了路易体,LBD患者还经常有淀粉样斑块
以及阿尔茨海默氏症的标志性神经元缠结,阿尔茨海默氏症患者
除了斑块和缠结外,通常还有路易体。aSyn如何成为
错误折叠以及为什么认知能力下降在DLB中加速尚不清楚。遗传学研究表明
DLB风险增加与编码载脂蛋白E的基因的APOE 4变体之间的关系,
这也是阿尔茨海默病风险的核心。我们报道了表达APOE 4的小鼠,
与其他APOE基因型相比,人APOE基因加速了aSyn聚集和早期死亡。
这一发现与在小鼠模型中表达人APOE基因型时观察到的效果相似
老年痴呆症的症状。我们的初步数据表明,星形胶质细胞和小胶质细胞摄取aSyn聚集体,
并通过内溶酶体途径处理它们,这可能是一种补偿机制,
降解有害的aSyn聚集体。我们建议检查aSyn聚集体的细胞生物转运
通过星形胶质细胞和小胶质细胞中的内溶酶体途径,并确定在这方面是否存在差异。
与APOE基因型有关的运输。我们假设APOE 4基因型损害内溶酶体,
星形胶质细胞和小胶质细胞中aSyn聚集体的降解,以及星形胶质细胞中APOE 4的表达,
特定的驱动加速aSyn病理,导致脑功能障碍和神经变性。我们将测试
无论这种作用是否主要由于星形胶质细胞或小胶质细胞自身内的细胞自主变化而发生,
包括与这些细胞中基因表达的变化有关,或者是否通过分泌介导,
已知载脂蛋白E蛋白颗粒通过与神经元和神经元上的受体结合而具有作用,
神经胶质。这些实验的主要目的是阐明APOE基因型如何调节内溶酶体加工
aSyn在星形胶质细胞和小胶质细胞中的作用,以及如何利用这些知识来开发新的治疗方法,
DLB,阿尔茨海默病和其他相关痴呆症。
项目成果
期刊论文数量(0)
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Albert A Davis其他文献
Albert A Davis的其他文献
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{{ truncateString('Albert A Davis', 18)}}的其他基金
ApoE Regulation of Alpha-Synuclein Pathology in Parkinson Disease Dementia
ApoE 对帕金森病痴呆中 α-突触核蛋白病理学的调节
- 批准号:
9295190 - 财政年份:2017
- 资助金额:
$ 165.84万 - 项目类别:
ApoE Regulation of Alpha-Synuclein Pathology in Parkinson Disease Dementia
ApoE 对帕金森病痴呆中 α-突触核蛋白病理学的调节
- 批准号:
10006865 - 财政年份:2017
- 资助金额:
$ 165.84万 - 项目类别:
ApoE Regulation of Alpha-Synuclein Pathology in Parkinson Disease Dementia
ApoE 对帕金森病痴呆中 α-突触核蛋白病理学的调节
- 批准号:
10216360 - 财政年份:2017
- 资助金额:
$ 165.84万 - 项目类别:
ApoE Regulation of Alpha-Synuclein Pathology in Parkinson Disease Dementia
ApoE 对帕金森病痴呆中 α-突触核蛋白病理学的调节
- 批准号:
9455808 - 财政年份:2017
- 资助金额:
$ 165.84万 - 项目类别:
Muscarinic Acetylcholine Receptors and Alzheimer's Disease Pathogenesis
毒蕈碱乙酰胆碱受体与阿尔茨海默病发病机制
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7275487 - 财政年份:2007
- 资助金额:
$ 165.84万 - 项目类别:
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