MECHANISMS OF APOLIPOPROTEIN E-INDUCED NEUROPROTECTION

中风是导致死亡的主要原因，也是中风的主要来源 残疾和痛苦。阿尔茨海默病是S病最常见的病因 老年痴呆症，据估计美国有400万人患有痴呆症 独自一人。载脂蛋白E已被确定为一种调节剂或易感性 这两种疾病的基因。在三种常见的载脂蛋白E亚型中，载脂蛋白E4是 与中风后的不良结局、创伤性脑损伤有关， 脑内出血，是阿尔茨海默病的主要危险因素 可能还有血管性痴呆症。相比之下，Apo E3和Apo E2亚型是 具有保护性，并与这些疾病的较低风险相关。类似 在载脂蛋白E转基因小鼠中进行了观察。的长期目标是 本研究旨在阐明载脂蛋白E发挥上述作用的分子机制。 大脑中的异构体特异性效应，特别是载脂蛋白E3是如何 具有神经保护作用。 初步结果表明，载脂蛋白E3和较小程度的载脂蛋白E4 刺激神经保护性蛋白酶抑制物纤溶酶原的合成 激活物抑制物1(PAI-1)的体外表达及其对小鼠的保护作用 不同形式的神经退行性变很可能是通过抑制丝氨酸蛋白酶 组织纤溶酶原激活物(TPA)。TPA可能是最丰富的蛋白水解酶 在大脑中，它会导致小鼠甚至可能是人类的神经退化。 因此，研究人员假设载脂蛋白E3激活了一种信号 导致PAI-1产生的途径，从而保护神经元 抗损伤，而载脂蛋白E4诱导的PAI-1较少，不起保护作用 有效对抗神经退行性变。 建议的研究旨在评估载脂蛋白E在体内的这一新功能 脑损伤和神经保护。在具体目标#1中，载脂蛋白E如何诱导PAI-1 将在分子水平上决定。在目标2中，载脂蛋白E对PAI-1的诱导 它对神经毒性的影响将在细胞培养中进行检测。在AIM #3，将在体内评估载脂蛋白E的神经保护作用。这些结果 可能有助于设计新的治疗策略来模仿有益的载脂蛋白E3 影响或抑制脑损伤中有害的载脂蛋白E4效应 神经退行性变。

Stroke is a leading cause of death and a major source of disability and suffering. Alzheimer' s disease is the most frequent cause of dementia in the elderly, affecting an estimated four million people in the US alone. Apolipoprotein E has been identified as a modulator or a susceptibility gene in both these diseases. Of the three common Apo E isoforms, Apo E4 is associated with poor outcome after stroke, traumatic brain injury, intracerebral hemorrhages, and is a major risk factor for Alzheimer's disease and possibly vascular dementia. In contrast, Apo E3 and Apo E2 isoforms are protective and associated with lower risk for these diseases. Similar observations were made in Apo E transgenic mice. The long-term objective of this study is to elucidate the molecular mechanism by which Apo E exerts these isoform-specific effects in the brain and specifically how Apo E3 is neuroprotective. The preliminary results show that Apo E3 and to a lesser extent Apo E4 stimulates the synthesis of a neuroprotective protease inhibitor, plasminogen activator inhibitor 1 (PAI-1) in vitro and that PAI-1 protects mice against different forms of neurodegeneration most likely by inhibiting serine protease tissue plasminogen activator (tPA). TPA is probably the most abundant protease in the brain and it cause neurodegeneration in mice and possibly humans. Therefore, the investigators hypothesize that Apo E3 activates a signaling pathway that leads to the production of PAI-1, which then protects neurons against injury, whereas Apo E4 induces less PAI-1 and does not protect efficiently against neurodegeneration. The proposed studies are designed to assess this novel function of Apo E in brain injury and neuroprotection. In Specific Aim #1, how Apo E induces PAI-1 will be determined at the molecular level. In Aim #2, apo E induction of PAI-1 and its influence on neurotoxicity will be examined in cell cultures. In Aim #3, the neuroprotective effect of Apo E will be assessed in vivo. These results may help devise novel therapeutic strategies to mimic the beneficial Apo E3 effects or inhibit the detrimental Apo E4 effects in brain injury and neurodegeneration.