Mechanisms of Age-Related Microglial Impairment and Rejuvenation in Alzheimer's Disease
阿尔茨海默病中与年龄相关的小胶质细胞损伤和复兴的机制
基本信息
- 批准号:9608519
- 负责人:
- 金额:$ 4.31万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-08-02 至 2021-08-01
- 项目状态:已结题
- 来源:
- 关键词:Abeta clearanceAffectAffinity ChromatographyAgeAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease riskAmyloidAmyloid beta-ProteinAnti-CD22ApoptoticBindingBinding ProteinsBiochemical GeneticsBlocking AntibodiesBrainBrain DiseasesBuffersCD22 geneCRISPR/Cas technologyCatalogsCause of DeathCell LineCell surfaceCellsClinicalDataDepositionDevelopmentDiseaseElderlyEtiologyFDA approvedFailureFunctional disorderGenesGeneticHealthHistologyHomeostasisImmuneImmunoglobulinsImpaired cognitionImpairmentIncidenceIndividualKnock-outLearningLectinMass Spectrum AnalysisMeasuresMediatingMemoryMicrogliaModalityModificationMonoclonal Antibody TherapyMusNerve DegenerationNeurodegenerative DisordersPathogenesisPathologicPatientsPhagocytesPhagocytosisPhagocytosis InhibitionPhenotypePolysaccharidesPopulationPredisposing FactorPrevalenceProteinsReceptors, Antigen, B-CellRegulationRejuvenationRoleSialic AcidsSignal TransductionSignal Transduction PathwaySynapsesSynaptosomesTherapeuticTissuesUnited Statesage relatedagedaging brainbasecell motilitycell typecognitive functiondisorder riskeffective therapyexperimental studyfeedingfitnessgenetic variantimmunoregulationimprovedmacrophagemouse modelnormal agingpathogenpreventreceptorsialic acid binding Ig-like lectinsialic acid receptorsmall moleculetherapeutic targettool
项目摘要
Project Summary
Age is the main risk factor for Alzheimer’s disease (AD), a neurodegenerative disorder rapidly increasing in
both incidence and prevalence as the population becomes older. Unfortunately, AD is the only top ten cause of
death with no effective treatments. Therefore, the development of disease-altering treatments for AD is an
urgent and unmet need. Although the exact etiology of AD is unknown, microglia, the tissue-resident
macrophages of the brain, have been implicated in disease pathogenesis based on the observation that
genetic variants in several microglia-specific genes significantly alter disease risk. In the healthy brain,
microglia maintain homeostasis through multiple modalities including phagocytic clearance of pathogens,
apoptotic cells, and debris. In AD brains and age-matched clinically-unimpaired brains alike, microglia are
dystrophic, hypo-motile, and burdened with lysosomal deposits indicative of impaired phagocytic degradation
of debris. These findings suggest that the general decline in phagocytosis with age might underlie pathological
neurodegeneration. However, the mechanisms of age-related microglial dysfunction are poorly understood.
This proposal aims to elucidate the mechanisms of impaired microglial phagocytosis in the aging brain and to
uncover therapeutic strategies to reverse this impairment in AD. Preliminary data suggest that cell-surface
sialic acid, an immunomodulatory glycan modification, inhibits phagocytosis in aged microglia. Aim 1 combines
biochemical and genetic tools to identify upstream and downstream signaling partners that transduce the anti-
phagocytic effect of sialic acid on aged microglia. Aim 2 will evaluate the therapeutic potential of blocking the
interaction between cell-surface sialic acid and its cognate receptor on microglia to promote phagocytosis and
ameliorate cognitive decline in a mouse model of AD. These experiments will elucidate a mechanism of
microglial dysfunction during normal aging with direct translational implications for patients with AD.
项目摘要
年龄是阿尔茨海默病(AD)的主要危险因素,AD是一种神经退行性疾病,在
随着人口老龄化,发病率和流行率都有所下降。不幸的是,AD是唯一排名前十的原因
在没有有效治疗的情况下死亡。因此,开发AD的疾病改变治疗方法是一种
迫切的和未得到满足的需求。尽管阿尔茨海默病的确切病因尚不清楚,但组织驻留的小胶质细胞
大脑的巨噬细胞,已经被认为与疾病的发病机制有关,这是基于观察到的
几个小胶质细胞特异性基因的遗传变异显著改变了疾病风险。在健康的大脑中,
小胶质细胞通过多种方式维持动态平衡,包括吞噬清除病原体,
凋亡的细胞和碎片。在阿尔茨海默病和年龄匹配的临床正常脑中,小胶质细胞
营养不良,活动不足,并有溶酶体沉积,表明吞噬细胞降解受损
碎片的碎片。这些发现表明,随着年龄的增长,吞噬功能的普遍下降可能是病理性的基础。
神经退行性变。然而,与年龄相关的小胶质细胞功能障碍的机制却知之甚少。
这一建议旨在阐明衰老脑中小胶质细胞吞噬功能受损的机制,并
发现逆转AD患者这种损害的治疗策略。初步数据显示,细胞表面
唾液酸是一种免疫调节的糖链修饰物,可抑制衰老小胶质细胞的吞噬作用。AIM 1联合收割机
生化和遗传工具,以确定上游和下游的信号伙伴,转导反式
唾液酸对衰老小胶质细胞的吞噬作用。目的2将评估阻断的治疗潜力
细胞表面唾液酸与其同源受体相互作用促进小胶质细胞吞噬功能
改善阿尔茨海默病小鼠模型的认知衰退。这些实验将阐明一种
正常衰老过程中的小胶质细胞功能障碍对AD患者有直接的翻译意义。
项目成果
期刊论文数量(0)
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