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）：在创伤性脑损伤（TBI）后，人类 APOE-¿ APOE4 基因多态性与死亡率增加、昏迷时间延长、预后不良以及迟发性阿尔茨海默氏病 (AD) 风险增加有关。APOE4 基因存在于 27% 的美国人口中，因此会影响到这一点。据估计，每年有 459,000 例 TBI 病例，目前尚不清楚 APOE4 基因型如何对 TBI 后的结果产生负面影响，也不知道是否需要基因型特异性治疗来改善 TBI 的累积和预后。称为淀粉样蛋白的神经毒性肽的沉积 -¿ (A¿). 大约 30% 的致命性 TBI 病例出现 A¿斑块，但是 A¿ 的沉积取决于患者的 APOE 基因型，只有 10% 的非 APOE4 大脑具有 A¿损伤后斑块，而 35% 的杂合 APOE4 大脑和 100% 的纯合 APOE4 大脑会形成 A¿ APOE 基因编码载脂蛋白 E (apoE) 蛋白，最近显示该蛋白可促进 A¿这些数据表明携带 APOE4 基因型的个体无法清除多余的 A¿这是由于 TBI 积累而产生的。已知会导致神经细胞凋亡并引发神经炎症。我们最近证明可以预防 A¿生产，或增强A¿清除，可以改善继发性损伤并预防小鼠实验性 TBI 引起的认知和运动缺陷。在这里，我们将研究 A¿ 中 apoE 亚型的作用。我们正在检验 apoE 在 A¿ 中发挥作用的假设。 TBI 后降解，但 apoE4 异构体在此过程中功能失调，我们认为 A¿ 的积累。 APOE4 小鼠中的 ApoE 导致损伤后细胞死亡增加以及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 apoE 在 A¿ TBI 后清除 目标 2) 确定 APOE 基因型对 A¿ 的影响TBI 后清除目标 3) 测试 APOE4 携带者 TBI 后较差的预后是否是由于 A¿这些积累数据将使我们能够确定 A¿ TBI 后 APOE4 患者体内会大量积聚，以及该 A 的功能后果积累。