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: 8608016
• 负责人: MARK P BURNS
• 金额: $ 38.72万
• 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/8608016
• 关键词: Ablation; Acute; Affect; Amyloid; Amyloid beta-Protein; 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; peptide A; 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（由申请人提供）：创伤性脑损伤（TBI）后，人类APOE-4（APOE 4）基因多态性与死亡率增加、昏迷时间增加、预后不良和迟发性阿尔茨海默病（AD）风险增加相关。APOE 4基因存在于27%的美国人口中，因此每年影响估计459，000例TBI病例。目前尚不清楚APOE 4基因型如何对TBI后的结果产生负面影响，或者是否需要基因型特异性治疗来改善预后。TBI导致一种称为淀粉样蛋白（A）的神经毒性肽的积累和沉积。大约30%的致命性TBI病例存在A？斑块，然而A？的沉积取决于患者的APOE基因型。只有10%的非APOE 4大脑在损伤后有A？斑块，而35%的杂合APOE 4大脑和100%的纯合APOE 4大脑会出现A？斑块。载脂蛋白E基因编码载脂蛋白E（apoE）蛋白，该蛋白最近被证明有助于A？的酶降解。这些数据表明，携带APOE 4基因型的个体无法清除由于TBI而产生的过量A？。已知过量A？的积累会导致神经元凋亡并引发神经炎症。我们最近已经证明，防止A <$生产，或提高A <$清除，可以改善继发性损伤，并防止小鼠实验性TBI引起的认知和运动缺陷。在这里，我们将研究载脂蛋白E异构体在TBI后A？清除中的作用。我们正在测试的假设，即载脂蛋白E是工具，在TBI后的A ²降解，但载脂蛋白E4亚型是功能障碍，在这个过程中。我们认为，APOE 4小鼠中A？的积累导致损伤后细胞死亡增加，功能和认知结果较差。我们将在我们的具体目标中检验这一假设：目标1）确定载脂蛋白E在TBI后A <$清除中的作用目标2）确定载脂蛋白E基因型对TBI后A <$清除的影响目标3）检验载脂蛋白E 4携带者TBI后预后较差是否是由于A <$积累延长。这些数据将使我们能够确定A <$的机制。在TBI后APOE 4患者中积极积累，以及A？积累的功能后果。