ApoE4, Neurovascular Injury and Cognitive Impairment
ApoE4、神经血管损伤和认知障碍
基本信息
- 批准号:10593979
- 负责人:
- 金额:$ 83.07万
- 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:2022-04-01 至 2027-03-31
- 项目状态:未结题
- 来源:
- 关键词:AbbreviationsAge-associated memory impairmentAgingAllelesAlzheimer&aposs DiseaseAlzheimer&aposs disease related dementiaAlzheimer&aposs disease riskApolipoprotein EAstrocytesAutomobile DrivingBilateralBlood VesselsBlood brain barrier dysfunctionBlood flowBone MarrowBrainBrain Hypoxia-IschemiaCarotid StenosisCarrier ProteinsCell secretionCellsCerebrovascular CirculationCerebrovascular DisordersCerebrumChimera organismCognitiveConsensusCorpus CallosumDementiaDevelopmentDichloromethylene DiphosphonateEndowmentEnzymesExhibitsFemaleFluorescenceFunctional disorderGene TargetingGeneticHistopathologyHumanHypoxiaImageImpaired cognitionIndividualInflammationInflammatoryInternationalKnowledgeLDL-Receptor Related Protein 1LeptomeningesLesionMacrophageMacrophage ActivationMediatingModelingMolecularMusMyelogenousMyeloid CellsNeocortexOxidative StressPenetrationPerfusionPhotonsPlayPredispositionProductionReactive Oxygen SpeciesRegulationRiskRisk FactorsRoleSourceTestingUnited States National Institutes of HealthVariantVascular Cognitive ImpairmentVascular DiseasesVentricularWhite Matter DiseaseWorkapolipoprotein E-3apolipoprotein E-4autocrinebaseblood-brain barrier disruptionblood-brain barrier permeabilizationcerebrovascularcognitive functioncognitive testingexperimental studygenetic risk factorgenetic variantinsightischemic injurylipid transportmalemouse modelneocorticalneurovascularneurovascular injurynew therapeutic targetnovelnovel strategiesreceptorsextherapeutic targetvascular cognitive impairment and dementiavascular factorwhite matterwhite matter damagewhite matter injury
项目摘要
ApoE is a lipid transport protein enriched in brain and present in three allelic variants (e2, e3, e4).
Homozygosity for the e4 allele (e4/e4) is the main genetic risk factor for Alzheimer’s disease, but
ApoE4 carriers also have increased risk for white matter lesions in both vascular cognitive
impairment and Alzheimer’s disease and related dementias. Subcortical and periventricular white
matter damage is a major cause of age-related cognitive impairment, but the mechanisms remain
elusive. Located at the borderzone between separate arterial territories, the deep white matter is
highly vulnerable to hypoxia-ischemia. ApoE4 carriers have reduced cerebral blood flow, whereas
mice expressing human ApoE4 exhibit a profound disruption of key mechanisms regulating the
delivery of blood flow to the brain. These findings raise the possibility that such cerebrovascular
dysregulation renders the deep white matter more susceptible to hypoxia-ischemia. Perivascular
macrophages (PVM), brain resident myeloid cells closely apposed to the outer wall of cerebral
pial and penetrating vessels, can produce ApoE, are enriched in ApoE receptors, and are a
powerful source of vascular oxidative stress and inflammation. Therefore, we hypothesize that
PVM-derived ApoE4 acts in an autocrine manner on PVM to produce vascular oxidative stress
and inflammation, leading to neurovascular dysfunction and increased susceptibility to white
matter injury. Since NOX2 is the main source of reactive oxygen species in macrophages and
TRPM2 channels are critical for macrophage activation and neurovascular dysfunction, we will
also examine their role. We will test the following hypotheses: (a) PVM are both a source and
target of the ApoE4 mediating neurovascular dysfunction; (b) PVM TRPM2 channels and NOX2
mediate ApoE4-induced vascular oxidative stress and inflammation leading to neurovascular
dysfunction; (c) PVM-derived ApoE4 is responsible for the increased susceptibility to oligemic
WM damage through NOX2 and TRPM2 channels. Studies are conducted in young and old mice
of both sexes with targeted replacement of mouse ApoE with human ApoE3 or 4. Deep white
matter injury is produced in the corpus callosum by bilateral carotid artery stenosis using
microcoils. Cutting-edge approaches are used, including 3-photon excited fluorescence to image
the deep white matter and a novel mouse model enabling conditional gene targeting in PVM.
These approaches allow us to assess microvascular perfusion and damage in the deep white
matter in mice with ApoE4, NOX2, or TRPM2 deletion in PVM. These studies will provide insight
into the mechanisms underlying the impact of ApoE4 on white matter damage and may unveil
new therapeutic targets for one of the leading causes of cognitive impairment and dementia.
载脂蛋白E是一种富含于脑内的脂质运输蛋白,存在三种等位基因变体(e2、e3、e4)。
E4等位基因纯合(e4/e4)是阿尔茨海默病的主要遗传风险因素,但
ApoE4携带者也增加了认知血管白质损害的风险
损害和阿尔茨海默病以及相关的痴呆。皮质下和脑室周围白色
物质损伤是与年龄相关的认知障碍的主要原因,但其机制仍然
难以捉摸。位于不同动脉区域之间的交界处,深层白质是
极易受缺氧和缺血的影响。载脂蛋白E4携带者脑血流量减少,而
表达人载脂蛋白E4的小鼠表现出调控人类载脂蛋白E4的关键机制的深刻破坏
将血液输送到大脑。这些发现增加了这样一种可能性,即
调节失调使深层白质更容易受到缺氧缺血的影响。血管周围
巨噬细胞(PVM)是与大脑外壁紧密相对的脑内髓系细胞
膜和穿透血管,可产生载脂蛋白E,富含载脂蛋白E受体,是一种
血管氧化应激和炎症的强大来源。因此,我们假设
PVM来源的ApoE4以自分泌方式作用于PVM产生血管氧化应激
和炎症,导致神经血管功能障碍和对白人的易感性增加
物质损伤。由于NOX2是巨噬细胞内活性氧的主要来源,
TRPM2通道是巨噬细胞激活和神经血管功能障碍的关键,我们将
也要审视他们的角色。我们将检验以下假设:(A)PVM既是源又是源
载脂蛋白E4介导神经血管功能障碍的靶点;(B)PVM、TRPM2通道和NOX2
介导载脂蛋白E4诱导的血管氧化应激和炎症导致神经血管
功能障碍;(C)PVM来源的ApoE4是导致少血症易感性增加的原因
通过NOX2和TRPM2通道造成的WM损伤。研究是在幼鼠和老年鼠身上进行的。
用人ApoE3或4.深白色靶向替换小鼠ApoE
用双侧颈总动脉狭窄造成的物质损伤
微线圈。使用了尖端的方法,包括三光子激发荧光成像
深白质和一种新的小鼠模型,使条件基因打靶在PVM。
这些方法使我们能够评估深白色的微血管灌注和损伤。
PVM中ApoE4、NOX2或TRPM2缺失的小鼠体内的物质。这些研究将提供洞察力
研究载脂蛋白E4对脑白质损伤影响的潜在机制,并可能揭示
针对认知障碍和痴呆症的主要原因之一的新治疗目标。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Costantino Iadecola其他文献
Costantino Iadecola的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Costantino Iadecola', 18)}}的其他基金
ApoE4, neurovascular injury and cognitive impairment
ApoE4、神经血管损伤和认知障碍
- 批准号:
10419353 - 财政年份:2022
- 资助金额:
$ 83.07万 - 项目类别:
High-speed imaging of cortical and white matter microvascular flow in AD/ADRD models
AD/ADRD 模型中皮质和白质微血管血流的高速成像
- 批准号:
10523289 - 财政年份:2022
- 资助金额:
$ 83.07万 - 项目类别:
Alzheimer's Disease Viewed as a Neurovascular Inflammatory Disorder
阿尔茨海默病被视为一种神经血管炎症性疾病
- 批准号:
9195011 - 财政年份:2016
- 资助金额:
$ 83.07万 - 项目类别:
ApoE4 and mechanisms of diffuse white matter injury
ApoE4 与弥漫性白质损伤的机制
- 批准号:
9756482 - 财政年份:2016
- 资助金额:
$ 83.07万 - 项目类别:
ApoE4 and mechanisms of diffuse white matter injury
ApoE4 与弥漫性白质损伤的机制
- 批准号:
9355719 - 财政年份:2016
- 资助金额:
$ 83.07万 - 项目类别:
ApoE4 and mechanisms of diffuse white matter injury
ApoE4 与弥漫性白质损伤的机制
- 批准号:
9264693 - 财政年份:2016
- 资助金额:
$ 83.07万 - 项目类别:
Dietary sodium, neurovascular dysfunction and cerebrovascular risk
膳食钠、神经血管功能障碍和脑血管风险
- 批准号:
10298081 - 财政年份:2015
- 资助金额:
$ 83.07万 - 项目类别:
Dietary Sodium, Neurovascular Dysfunction and Cerebrovascular Risk
膳食钠、神经血管功能障碍和脑血管风险
- 批准号:
10650322 - 财政年份:2015
- 资助金额:
$ 83.07万 - 项目类别:
相似海外基金
THE GENETICS AND FUNCTIONAL NEUROANATOMY OF AGE-ASSOCIATED MEMORY IMPAIRMENT
年龄相关记忆障碍的遗传学和功能神经解剖学
- 批准号:
7606738 - 财政年份:2007
- 资助金额:
$ 83.07万 - 项目类别:
THE GENETICS AND FUNCTIONAL NEUROANATOMY OF AGE-ASSOCIATED MEMORY IMPAIRMENT
年龄相关记忆障碍的遗传学和功能神经解剖学
- 批准号:
7717960 - 财政年份:2007
- 资助金额:
$ 83.07万 - 项目类别:
THE GENETICS AND FUNCTIONAL NEUROANATOMY OF AGE-ASSOCIATED MEMORY IMPAIRMENT
年龄相关记忆障碍的遗传学和功能神经解剖学
- 批准号:
7205360 - 财政年份:2004
- 资助金额:
$ 83.07万 - 项目类别:
CITICOLINE AND AGE ASSOCIATED MEMORY IMPAIRMENT
胞二磷胆碱与年龄相关的记忆障碍
- 批准号:
6305687 - 财政年份:1999
- 资助金额:
$ 83.07万 - 项目类别:
CITICOLINE AND AGE ASSOCIATED MEMORY IMPAIRMENT
胞二磷胆碱与年龄相关的记忆障碍
- 批准号:
6115572 - 财政年份:1998
- 资助金额:
$ 83.07万 - 项目类别:
A study on the biological features of age-associated memory impairment (AAMI).
年龄相关记忆障碍(AAMI)生物学特征的研究。
- 批准号:
09671003 - 财政年份:1997
- 资助金额:
$ 83.07万 - 项目类别:
Grant-in-Aid for Scientific Research (C).
CITICOLINE AND AGE ASSOCIATED MEMORY IMPAIRMENT
胞二磷胆碱与年龄相关的记忆障碍
- 批准号:
6276806 - 财政年份:1997
- 资助金额:
$ 83.07万 - 项目类别:
AGE-ASSOCIATED MEMORY IMPAIRMENT: COMMUNITY-BASED STUDY
与年龄相关的记忆障碍:基于社区的研究
- 批准号:
3386469 - 财政年份:1990
- 资助金额:
$ 83.07万 - 项目类别:
AGE-ASSOCIATED MEMORY IMPAIRMENT: COMMUNITY-BASED STUDY
与年龄相关的记忆障碍:基于社区的研究
- 批准号:
3386468 - 财政年份:1990
- 资助金额:
$ 83.07万 - 项目类别:
AGE-ASSOCIATED MEMORY IMPAIRMENT: COMMUNITY-BASED STUDY
与年龄相关的记忆障碍:基于社区的研究
- 批准号:
2247160 - 财政年份:1990
- 资助金额:
$ 83.07万 - 项目类别:














{{item.name}}会员




