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

描述（由申请人提供）：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、预后不良和迟发性阿尔茨海默病（AD）风险增加相关。27%的美国人携带APOE4基因，每年约有45.9万例TBI病例受其影响。目前尚不清楚APOE4基因型如何对TBI后的预后产生负面影响，也不清楚是否需要基因型特异性治疗来改善预后。创伤性脑损伤引起一种叫做淀粉样蛋白- (a)的神经毒性肽的积累和沉积。在所有致死性脑外伤病例中，约30%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APOE4大脑在损伤后会产生A -斑块，而35%的杂合APOE4大脑和100%的纯合APOE4大脑会产生A -斑块。APOE基因编码载脂蛋白E （APOE）蛋白，该蛋白最近被证明可以促进A¿的酶降解。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¿。已知过量A¿的积累会导致神经元凋亡并引发神经炎症。我们最近的研究表明，阻止A¿的产生或增强A¿的清除，可以改善小鼠的继发性损伤，预防实验性脑外伤引起的认知和运动缺陷。在这里，我们将研究apoE异构体在脑外伤后A¿清除中的作用。我们正在测试apoE在脑外伤后A¿降解中起作用的假设，但apoE4亚型在这一过程中功能失调。我们认为，APOE4小鼠中A¿的积累导致细胞死亡增加，损伤后功能和认知结果变差。我们将在我们的具体目标中验证这一假设：目标1)确定apoE在TBI Aim后A¿清除中的作用2)确定apoE基因型对TBI Aim后A¿清除的影响3)测试APOE4携带者TBI后较差的预后是否是由于A¿积累的延长这些数据将使我们能够确定A¿在APOE4患者TBI后积极积累的机制，以及A¿积累的功能后果。

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.