Defining the role of perineuronal nets in Alzheimer's Disease pathology
定义神经周围网在阿尔茨海默病病理学中的作用
基本信息
- 批准号:10679795
- 负责人:
- 金额:$ 4.32万
- 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:2023-07-01 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:AblationAccelerationAffectAgeAllelesAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease pathologyBehavioralBrainCell DeathCellsCentral Nervous SystemCerebral hemisphereChondroitin Sulfate AChondroitin Sulfate ProteoglycanCognitive deficitsCytoprotectionDataDementiaDepositionDevelopmentDiseaseElderlyEnhancersEnterobacteria phage P1 Cre recombinaseExhibitsExtracellular MatrixFluorescent in Situ HybridizationGenesGenetic RecombinationHippocampusHomeostasisImmunohistochemistryImmunologic SurveillanceImpaired cognitionImpairmentIncubatedInjectionsInterneuronsKnowledgeLaboratory FindingLearningLoxP-flanked alleleMacrophageMediatingMediatorMemoryMemory impairmentMicrogliaMinorModelingMusNeurodegenerative DisordersNeurofibrillary TanglesNeuronal DysfunctionNeuronsNeurotoxinsOutcomeOxidative StressParvalbuminsPathogenesisPathologicPathologyPatientsPlayPopulationPredispositionProtease InhibitorProtein AnalysisProteinsRegulationRoleSenile PlaquesStructureSynapsesTherapeuticTimeTissuesTransgenic OrganismsViral VectorVirusWild Type Mouseage relatedaggrecaneffective therapygenome wide association studyhuman tissuein vivoinhibitor therapyinhibitory neuroninsightknockout genememory consolidationmouse modelnestin proteinneuroinflammationneuron lossneuronal cell bodynovel therapeuticspreventtranscriptome sequencing
项目摘要
Project Summary
Alzheimer’s Disease (AD) is the most common cause of dementia in elderly populations. The development of
effective treatments for this progressive neurodegenerative disorder has been hindered by our lack of
understanding of the disease. AD is classically characterized by amyloid-β (Aβ) plaques, neurofibrillary tangles,
and brain-wide neuroinflammation which ultimately result in synaptic loss, neuronal dysfunction, and cognitive
impairments. With our incomplete knowledge of the mechanisms underlying the emergence of these pathological
hallmarks, we must focus on understanding the different aspects of disease pathology to successfully create
therapies treating AD. Genome wide association studies (GWAS) have implicated microglia, the tissue-resident
macrophages of the brain, as mediators of disease pathogenesis. Microglia actively maintain tissue homeostasis
in the healthy brain including the regulation of lattice-like extracellular matrix (ECM) structures called
perineuronal nets (PNNs). PNNs enwrap the soma and proximal synapses of different neuronal subsets and aid
in learning/memory consolidation. While PNNs are naturally lost with age in wild-type (WT) mice, this loss is
exacerbated in AD. Interestingly, when microglia are eliminated in the AD transgenic 5xFAD mouse model, 1)
plaques fail to form and 2) PNN loss is prevented, altogether suggesting PNNs play a protective role. However,
the consequences of PNN loss in AD remain unknown. To that end, we have developed two approaches to
ablate PNN structures both before and after the onset of plaque deposition in order to determine their role in
plaque formation, synaptic loss, and neuronal loss. In this proposal, I will determine the impact of PNNs in AD
pathology by pursuing two important questions: 1) does the loss of these ECM structures facilitate plaque
formation and 2) does PNN loss make neurons more susceptible to damage? Collectively, this proposal will
elucidate the role of PNNs in AD – before and after the onset of plaque pathology – by exploring how their
experimental ablation will affect plaque deposition, synaptic loss, and neuronal loss. Establishing whether PNNs
can prevent plaque deposition as well as determining whether PNN loss in AD renders neurons more susceptible
to damage is highly relevant and could lead to new therapeutic avenues that target genes/ proteins involved in
PNN synthesis and degradation.
项目总结
项目成果
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