Hartman Richard E, Laurer Helmut, Longhi Luca, Bales Kelly R, Paul Steven M, McIntosh Tracy K, Holtzman David M
Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
J Neurosci. 2002 Dec 1;22(23):10083-7. doi: 10.1523/JNEUROSCI.22-23-10083.2002.
The epsilon4 allele of apolipoprotein E (APOE) and traumatic brain injury (TBI) are both risk factors for the development of Alzheimer's disease (AD). These factors may act synergistically, in that APOE4+ individuals are more likely to develop dementia after TBI. Because the mechanism underlying these effects is unclear, we questioned whether APOE4 and TBI interact either through effects on amyloid-beta (Abeta) or by enhancing cell death/tissue injury. We assessed the effects of TBI in PDAPP mice (transgenic mice that develop AD-like pathology) expressing human APOE3 (PDAPP:E3), human APOE4 (PDAPP:E4), or no APOE (PDAPP:E-/-). Mice were subjected to a unilateral cortical impact injury at 9-10 months of age and allowed to survive for 3 months. Abeta load, hippocampal/cortical volumes, and hippocampal CA3 cell loss were quantified using stereological methods. All of the groups contained mice with Abeta-immunoreactive deposits (56% PDAPP:E4, 20% PDAPP:E3, 75% PDAPP:E-/-), but thioflavine-S-positive Abeta (amyloid) was present only in the molecular layer of the dentate gyrus in the PDAPP:E4 mice (44%). In contrast, our previous studies showed that in the absence of TBI, PDAPP:E3 and PDAPP:E4 mice have little to no Abeta deposition at this age. After TBI, all of the Abeta deposits present in PDAPP:E3 and PDAPP:E-/- mice were diffuse plaques. In contrast to the effect of APOE4 on amyloid, PDAPP:E3, PDAPP:E4, and PDAPP:E-/- mice did not differ in the amount of brain tissue or cell loss. These data support the hypothesis that APOE4 influences the neurodegenerative cascade after TBI via an effect on Abeta.
载脂蛋白E（APOE）的ε4等位基因和创伤性脑损伤（TBI）都是阿尔茨海默病（AD）发生发展的危险因素。这些因素可能协同作用，因为携带APOE4的个体在创伤性脑损伤后更易患痴呆症。由于这些作用的潜在机制尚不清楚，我们推测APOE4和TBI是否通过对β淀粉样蛋白（Aβ）的影响或通过增强细胞死亡/组织损伤而相互作用。我们评估了TBI对表达人类APOE3（PDAPP:E3）、人类APOE4（PDAPP:E4）或不表达APOE（PDAPP:E-/-）的PDAPP小鼠（发生类似AD病理改变的转基因小鼠）的影响。在9至10月龄时，对小鼠进行单侧皮质撞击损伤，并使其存活3个月。使用体视学方法对Aβ负荷、海马/皮质体积和海马CA3区细胞丢失进行定量分析。所有组中均有小鼠存在Aβ免疫反应性沉积物（56%的PDAPP:E4小鼠、20%的PDAPP:E3小鼠、75%的PDAPP:E-/-小鼠），但硫黄素-S阳性Aβ（淀粉样蛋白）仅在PDAPP:E4小鼠齿状回分子层中存在（44%）。相比之下，我们之前的研究表明，在没有TBI的情况下，这个年龄段的PDAPP:E3和PDAPP:E4小鼠几乎没有Aβ沉积。TBI后，PDAPP:E3和PDAPP:E-/-小鼠中所有的Aβ沉积物均为弥漫性斑块。与APOE4对淀粉样蛋白的影响不同，PDAPP:E3、PDAPP:E4和PDAPP:E-/-小鼠在脑组织量或细胞丢失方面没有差异。这些数据支持以下假说：APOE4通过对Aβ的影响来影响TBI后的神经退行性级联反应。
