MECHANISMS OF APOLIPOPROTEIN E-INDUCED NEUROPROTECTION

中风是导致死亡的主要原因，也是 残疾和痛苦。老年痴呆症是最常见的 老年痴呆症，在美国估计有400万人受到影响 一个人载脂蛋白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，创伤性脑损伤， 是阿尔茨海默病的主要危险因素 可能还有血管性痴呆与此相反，Apo E3和Apo E2同种型是 具有保护性，并与这些疾病的低风险相关。类似 在ApoE转基因小鼠中进行观察。的长期目标 本研究旨在阐明载脂蛋白E发挥这些作用的分子机制， 同种型在大脑中的特定作用，特别是载脂蛋白E3是如何 神经保护 初步结果表明，载脂蛋白E3和在较小程度上载脂蛋白E4 刺激神经保护性蛋白酶抑制剂纤溶酶原的合成 激活物抑制剂1（派-1）的体外研究，派-1保护小鼠免受 不同形式的神经变性最有可能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酶 它会导致老鼠甚至人类的神经退化。 因此，研究人员假设载脂蛋白E3激活了一种信号传导， 导致派-1产生的途径，然后保护神经元 而Apo E4诱导的派-1较少， 有效对抗神经退化 拟议的研究旨在评估载脂蛋白E的这种新功能， 脑损伤和神经保护。在特定目标#1中，Apo E如何诱导派-1 将在分子水平上决定。在目标#2中，派-1的apo E诱导 并将在细胞培养物中检查其对神经毒性的影响。在Aim中 #3，将在体内评估Apo 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，以模拟有益的载脂蛋白E3， 影响或抑制脑损伤中的有害Apo E4作用， 神经变性

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.