The role of apoE and APOE genotype in amyloid-beta clearance after TBI

apoE 和 APOE 基因型在 TBI 后β-淀粉样蛋白清除中的作用

• 批准号: 8729697
• 负责人: MARK P BURNS
• 金额: $ 3.17万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8729697
• 关键词: Ablation; Acute; Affect; Amyloid; Amyloid beta-Protein; Amyloid deposition; Apolipoprotein E; Behavioral; Brain; Cell Death; Cognitive; Cognitive deficits; Coma; Data; Deposition; E protein; Excision; Figs - dietary; Genes; Genetic; Genetic Polymorphism; Genotype; Human; Individual; Inflammation; Injury; Late Onset Alzheimer Disease; Lesion; Mediator of activation protein; Mus; Outcome; Patients; Peptides; Pharmacological Treatment; Population; Process; Production; Protein Isoforms; Proteins; Risk; Role; Secondary to; Testing; Therapeutic; Time; Traumatic Brain Injury; Visit; apolipoprotein E-3; apolipoprotein E-4; base; functional outcomes; improved; in vivo; mortality; motor deficit; neuroinflammation; neuron apoptosis; neuron loss; neurotoxic; outcome forecast; prevent; public health relevance; theories

DESCRIPTION (provided by applicant): After traumatic brain injury (TBI) the human APOE-¿4 (APOE4) gene polymorphism is associated with increased mortality, increased coma time, poor prognosis, and an increased risk of late-onset Alzheimer's disease (AD). The APOE4 gene is found in 27% of the US population, and as such affects an estimated 459,000 TBI cases each year. It is not known how APOE4 genotype negatively impacts outcome after TBI, or if genotype-specific treatments are required to improve prognosis. TBI causes the accumulation and deposition of a neurotoxic peptide called amyloid-¿ (A¿). Approximately 30% of all fatal TBI cases present with A¿ plaques, however the deposition of A¿ is dependent on the APOE genotype of the patient. Only 10% of non-APOE4 brains have A¿ plaques after injury, while 35% of heterozygous APOE4 brains, and 100% of homozygous APOE4 brains, develop A¿ plaques. The APOE gene encodes for the apolipoprotein E (apoE) protein, which was recently shown to facilitate the enzymatic degradation of A¿. These data suggest that individuals carrying the APOE4 genotype are unable to clear the excess A¿ that is produced as a result of TBI. Accumulation of excess A¿ is known to cause neuronal apoptosis and trigger neuroinflammation. We have recently shown that preventing A¿ production, or enhancing A¿ clearance, can ameliorate secondary injury and prevent cognitive and motor deficits caused by experimental TBI in mice. Here we will study the role of apoE isoforms in A¿ clearance after TBI. We are testing the hypothesis that apoE is instrumental in A¿ degradation after TBI, but the apoE4 isoform is dysfunctional at this process. We believe that the accumulation of A¿ in APOE4 mice leads to increased cell death and poorer functional and cognitive outcome after injury. We will test this hypothesis in our Specific Aims: Aim 1) Determine the role of apoE in A¿ clearance after TBI Aim 2) Determine the effect of APOE genotype on A¿ clearance after TBI Aim 3) Test if the poorer prognosis after TBI in APOE4 carriers is due to prolonged A¿ accumulation These data will allow us to determine the mechanism by which A¿ accumulates aggressively in APOE4 patients after TBI, and the functional consequences of that A¿ accumulation.

描述（由应用提供）：创伤性脑损伤（TBI）后，人类APOE-€4（APOE4）基因多态性与死亡率增加，昏迷时间增加，预后不良以及患阿尔茨海默氏病（AD）的风险增加有关。 APOE4基因在美国27％的人口中发现，因此每年估计有459,000个TBI病例。尚不清楚APOE4基因型如何对TBI后结果产生负面影响，或者是否需要基因型特异性治疗以改善预后。 TBI导致称为淀粉样蛋白的神经毒性肽的积累和沉积。大约30％的所有致命TBI病例中都有A斑块，但是A的沉积取决于患者的APOE基因型。受伤后，只有10％的非APOE4大脑有A斑块，而35％的杂合子APOE4大脑和100％的纯合子APOE4大脑会出现斑块。 APOE基因编码载脂蛋白E（APOE）蛋白，该蛋白最近被证明可促进A e酶的酶促降解。这些数据表明，携带APOE4基因型的个体无法清除由于TBI而产生的过量A。众所周知，过多的A累积会导致神经元细胞凋亡并触发神经炎症。我们最近表明，防止生产或增强清除率可以改善继发损伤，并防止小鼠实验性TBI引起的认知和运动定义。在这里，我们将研究APOE同工型在TBI之后清除中的作用。我们正在检验以下假设：APOE在TBI后有助于A降解，但是在此过程中，APOE4同工型具有功能障碍。我们认为，在APOE4小鼠中A的积累会导致细胞死亡增加，受伤后的功能和认知结果较差。我们将在我们的具体目的中检验这一假设：目标1）确定APOE在TBI目标后的清除率中的作用2）确定ApoE基因型对TBI AIM后APOE基因型对A的影响3）测试3）测试如果TBI在APOE4载体中TBI后较差的预后较差是否会导致AP延长A的延长，则这些数据会累积APE，并且在APE中累积了AP，并且在THE APER中累积了累积的机构，并且累积了累积的机构，并且会累积累积的机构，并且累积了累积的累积，并且会累积累积的累积。积累的后果。