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

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.
ApoE是一种富含大脑的脂质转运蛋白,存在于三种等位基因变体中(e2, e3, e4)。

项目成果

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Costantino Iadecola其他文献

Costantino Iadecola的其他文献

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{{ 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:
Hypertension and neurovascular dysfunction
高血压和神经血管功能障碍
  • 批准号:
    8908643
  • 财政年份:
    2015
  • 资助金额:
    $ 83.07万
  • 项目类别:
Hypertension and neurovascular dysfunction
高血压和神经血管功能障碍
  • 批准号:
    9915965
  • 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:
    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:

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  • 财政年份:
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