Identification and characterization of the CD31-ApoE-mCRP pathway for Alzheimer's disease in humans.

人类阿尔茨海默病 CD31-ApoE-mCRP 通路的鉴定和表征。

• 批准号: 10591027
• 负责人: Andrew EMILI
• 金额: $ 240.46万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-15 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591027
• 关键词: Alleles; Alzheimer' s Disease; Alzheimer' s Disease Pathway; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease risk; Apolipoprotein E; Binding; Binding Proteins; Biological Assay; Blood; Blood - brain barrier anatomy; Boston; Brain; Brain Pathology; C-reactive protein; Cell Aging; Cerebrovascular system; Cerebrum; Chronic; Cognitive; Data; Data Set; Diagnosis; Disease; Drug Targeting; Endothelial Cells; Endothelium; Exhibits; Foundations; Framingham Heart Study; Freezing; Genetic; Genotype; Human; Impaired cognition; Inflammation; Inflammatory; Inflammatory Response; Investigation; Knock-in Mouse; Ligation; Link; Magnetic Resonance Imaging; Measures; Mediating; Mus; Non-Steroidal Anti-Inflammatory Agents; Onset of illness; PECAM1 gene; Pathologic; Pathologic Processes; Pathology; Pathway interactions; Pattern; Peripheral; Peripheral Vascular Diseases; Phosphorylation; Proteins; Proteomics; Risk; Risk Reduction; Sampling; Signal Transduction; Source; Techniques; Therapeutic Intervention; Toxic effect; Universities; Vascular Endothelial Cell; apolipoprotein E-3; apolipoprotein E-4; brain endothelial cell; brain tissue; brain volume; cerebral microvasculature; cerebrovascular; cognitive change; cognitive function; effective therapy; extracellular; immunoreaction; mild cognitive impairment; mind control; monomer; mouse model; neuroinflammation; older patient; pre-clinical; precision genetics; preclinical study; preference; prognostic; receptor; transmission process; vascular injury

SUMMARY Our study discovered that elevated blood C-reactive protein (CRP) in Apolipoprotein E4 (ApoE4) carriers, but not in carriers of ApoE2 and ApoE3 alleles, increased the risk and shortened latency for Alzheimer’s disease (AD) onset (Tao et al. 2018). As both peripheral chronic inflammation and peripheral vascular disease increase AD risk, CRP is considered to be the major inflammatory response protein that mediates toxicity in peripheral vascular injuries/diseases through vascular endothelial cells. There are two species of CRP, pentameric oligoprotein (pCRP) and monomeric CRP (mCRP). Our preclinical study discovered that the receptor for mCRP, CD31 (Pecam1), is located on the blood-facing endothelial cells of the blood-brain barrier (BBB) and that mCRP acts to increase phosphorylation of the endothelial CD31 receptor (pCD31), transmitting signals and AD pathology in a pattern of ApoE4>ApoE3>ApoE2 (Zhang et al. 2021). However, whether mCRP is linked with cerebrovascular endothelial pathology leading to AD risk in humans is unclear. Our central hypothesis is that the mCRP-CD31 binding on brain endothelial cells will be associated with increased CD31 phosphorylation (pCD31) and neuroinflammation, with more severe cerebrovascular and AD pathologies, and with cognitive decline in an ApoE sensitive manner (ApoE4 > ApoE3 > ApoE2) in humans; this pathological process is counter acted by the ApoE-CD31 binding on endothelial cells in the brain. There are three aims. Aim 1 will establish the relationship between endothelial CD31 expression, CD31 phosphorylation and mCRP to AD risk in ApoE4 carriers using human brain tissues. Aim 2 will relate brain cerebrovascular expression of CD31, pCD31, and mCRP-CD31 and ApoE-CD31 bindings to incident cognitive change. Aim 3 will isolate microvessels from frozen brain tissues in each pathology group and apply phosphor-proteomics. We will further validate CD31 and its involved pathway(s) by using ApoE knock-in mice responding to peripheral elevated mCRP. Should our proposed study support the concept that mCRP through mCRP-CD31 vs. ApoE-CD31 binding is a mediating factor of ApoE4 to increase AD risk, it will lay foundation for a new, genetic based drug target for AD.

总结 我们的研究发现，载脂蛋白E4（ApoE 4） 携带者（但不是ApoE 2和ApoE 3等位基因携带者）增加了风险并缩短了潜伏期 阿尔茨海默病（AD）发作（Tao et al. 2018）。由于外周慢性炎症和 外周血管疾病增加AD风险，CRP被认为是主要的炎症反应 通过血管内皮细胞介导外周血管损伤/疾病毒性的蛋白质。 有两种CRP，五聚体寡蛋白（pCRP）和单体CRP（mCRP）。我们 临床前研究发现mCRP的受体CD 31（Pecam 1）位于面向血液的表面 血脑屏障（BBB）的内皮细胞，并且mCRP作用于增加血脑屏障（BBB）的磷酸化。 内皮CD 31受体（pCD 31），以一种模式传递信号和AD病理学， ApoE 4> ApoE 3> ApoE 2（Zhang等人，2021）。然而，mCRP是否与脑血管疾病有关， 导致人类AD风险的内皮病理学尚不清楚。我们的中心假设是， 脑内皮细胞上的mCRP-CD 31结合将与CD 31增加相关 磷酸化（pCD 31）和神经炎症，更严重的脑血管和AD 病理学，并以ApoE敏感方式（ApoE 4> ApoE 3> ApoE 2）伴认知功能减退 在人类中，这种病理过程通过ApoE-CD 31结合在内皮细胞上来抵消。 脑细胞。有三个目标。目的1建立内皮细胞CD 31与血管内皮细胞凋亡的关系。 使用人脑组织，在ApoE 4携带者中表达、CD 31磷酸化和mCRP与AD风险的关系。 目的2将脑血管中CD 31、pCD 31、mCRP-CD 31和ApoE-CD 31的表达与脑组织中CD 31、pCD 31、mCRP-CD 31和ApoE-CD 31的表达进行相关性研究 与认知变化的关联目标3将从每个人的冷冻脑组织中分离微血管 病理组和应用磷蛋白质组学。我们将进一步验证CD 31及其参与的 通过使用对外周升高的mCRP有反应的ApoE基因敲入小鼠，如果我们的 拟定的研究支持mCRP通过mCRP-CD 31与ApoE-CD 31结合的概念， ApoE 4介导因子增加AD风险，这将为新的基于基因的药物靶点奠定基础 对于AD。