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

描述(由申请人提供)：在创伤性脑损伤(TBI)后，人类载脂蛋白4(APOE4)基因多态与死亡率增加、昏迷时间增加、预后不良以及晚发性阿尔茨海默病(AD)风险增加有关。在27%的美国人口中发现了APOE4基因，因此估计每年影响459,000例脑损伤病例。目前尚不清楚APOE4基因型如何对脑外伤后的预后产生负面影响，也不清楚是否需要针对不同的基因型进行治疗以改善预后。脑外伤会导致一种名为淀粉样蛋白(A)的神经毒肽的积累和沉积。在所有致命性脑损伤病例中，大约30%存在A？斑块，然而A？的沉积取决于患者的APOE基因。只有10%的非APOE4大脑在损伤后有A？斑块，而35%的APOE4杂合子大脑和100%的纯合子APOE4大脑会发展成A？斑块。载脂蛋白E(ApoE)基因编码载脂蛋白E(ApoE)蛋白，近年来发现apoE蛋白可促进Aβ的酶降解。这些数据表明，携带APOE4基因的个体无法清除因脑外伤而产生的多余的A？已知过量的A？堆积会导致神经细胞凋亡并引发神经炎症。我们最近的研究表明，防止A‘的产生，或增强A’的清除，可以改善实验性脑损伤小鼠的继发性损伤，防止由实验性脑损伤引起的认知和运动障碍。在这里，我们将研究载脂蛋白E亚型在颅脑损伤后清除Aβ中的作用。我们正在验证一种假设，即apoE在脑外伤后的A？降解中起作用，但apoE4亚型在这一过程中功能障碍。我们认为，APOE4小鼠体内A‘的积累导致细胞死亡增加，并导致损伤后较差的功能和认知结果。我们将在我们的特定目标中测试这一假说：目的1)确定载脂蛋白E在脑损伤后A？清除中的作用目的2)确定APOE基因对脑损伤后A？清除的影响目的3)测试APOE4携带者在脑损伤后预后较差的原因是否由于A？的长期积聚这些数据将使我们能够确定在脑损伤后APOE4患者中A？的侵袭性积聚的机制，以及A？积聚的功能后果。

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.