Enhancing microglia-dependent plaque clearance in the Alzheimer disease brain by targeting Ifi27l2a expression
Enhancing microglia-dependent plaque clearance in the Alzheimer disease brain by targeting Ifi27l2a expression
批准号:
10214069
负责人:
GAB SEOK KIM
金额:
$42.9万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-05-15 至 2023-10-31
关键词:
Abeta clearanceAgeAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease pathologyAmyloidAmyloid beta-ProteinBlood VesselsBrainCell LineCerebral Amyloid AngiopathyDataDementiaDepositionDevelopmentDiagnosisDiseaseDown-RegulationEquilibriumExposure toFlow CytometryGene Expression ProfileGenesGenetic TranscriptionGliosisHumanImpairmentInflammatoryInterferon-alphaInterferonsIschemic StrokeLabelLatex BeadLightLiteratureMeasuresMediatingMessenger RNAMicroRNAsMicrogliaModelingMusNeurodegenerative DisordersNeuronsOntologyPathologicPathologyPathway interactionsPatientsPhagocytesPhagocytosisPhenotypePopulationProbabilityProcessProteinsRegulationRoleSamplingSenile PlaquesSmall Interfering RNAStimulusTestingTg2576Thalamic structureUp-Regulationabeta depositionage relatedagedbrain parenchymaeffectiveness testingin silicoin vivoknock-downmRNA Expressionmouse modelneuropathologynew therapeutic targetnovelnovel strategiesoverexpressionpredictive modelingpromoterprotein expressionresponsesingle cell analysissingle-cell RNA sequencingsmall hairpin RNAuptake
中文摘要
摘要
英文摘要
Abstract
Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA) are devastating aging-associated
neurodegenerative diseases which involve pathological deposition of amyloid-beta (Aβ) in the brain
parenchyma and around the leptomeningeal vasculature. Aβ uptake in microglia (MG) is strikingly
reduced with age, which may contribute to reduced amyloid clearance and increased plaque
accumulation. Recently, a novel subset of MG with a distinct gene expression signature (“disease-
associated microglia”; DAM) have emerged as a critical player in phagocytosis of Aβ in AD. Using
unbiased analysis of single-cell RNA sequencing (scRNAseq), we discovered that Interferon alpha-
inducible protein 27-like protein 2A (Ifi27l2a) is the most highly upregulated gene in MG following
ischemic stroke, with a greater increase in aging. Using this finding as a launch point, we then examined
if similar upregulation occurred in conditions of AD and CAA. We subsequently found that Ifi27l2a mRNA
expression is significantly elevated in the brain of symptomatic TgSwDI mice – a mouse model which
develops both vascular and parenchymal Aβ deposits. In human brain samples, we found significantly
elevated Ifi27l2a protein expression in MG in sections from patients with confirmed CAA and AD
pathology versus non-disease age-matched controls. We also found upregulation of Ifi27l2a in a human
microglial cell line (HMC3) following inflammatory challenge. Our scRNAseq analysis of the MG
population showed a positive correlation between Ifi27l2a expression and inflammatory genes and a
negative correlation with phagocytic (and DAM-identifying) genes. In light of our new findings regarding
the role of Ifi27l2a in MG/DAM phenotype and the known role of MG in Aβ clearance, we now propose
to explore the novel role of Ifi27l2a in regulating MG phagocytic function and Aβ clearance using a mouse
model which demonstrates both vascular and parenchymal amyloid plaque formation (TgSwDI).
We will test our model in which elevated Ifi27l2a expression in MG promotes reduced phagocytic capacity
and thus impaired clearance of Aβ. In aim 1, we will examine potential mechanisms of post-transcriptional
Ifi27l2a regulation. We will use primary MG (cultured from aged mouse brain) and a human MG cell line
to determine the contribution of two in silico predicted microRNAs on Ifi27l2a level and on resulting
phagocytic function. In aim 2, we will demonstrate the in vivo role of Ifi27l2a in regulating MG/DAM
phagocytic phenotype and determine the potential for Ifi27l2a down-regulation to promote enhanced
clearance of vascular and parenchymal Aβ plaques. For these studies, we will use TgSwDI mice at a
stage where Aβ vascular deposits and parenchymal plaques are evident. If successful, these studies
would provide the basis for new approaches for enhancing clearance of Aβ aggregates in the brain.
期刊论文(1)
专著(0)
科研奖励(0)
会议论文
DOI:
10.3390/ijms23168885
发表时间:
2022-08-10
期刊:
International journal of molecular sciences
影响因子:
5.6
作者:
[]
通讯作者:
Ifi27l2a as a therapeutic target for stroke
-
批准号:10719517
-
项目类别:
-
资助金额:$45.98万
-
财政年份:2023
-
负责人:GAB SEOK KIM
-
依托单位:
国内基金
海外基金
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