Human apolipoprotein E4 alters the amyloid-β 40:42 ratio and promotes the formation of cerebral amyloid angiopathy in an amyloid precursor protein transgenic model
Human apolipoprotein E4 alters the amyloid-β 40:42 ratio and promotes the formation of cerebral amyloid angiopathy in an amyloid precursor protein transgenic model
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DOI：
10.1523/jneurosci.5170-04.2005
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发表时间：
2005-03-16
影响因子：
5.3
通讯作者：
Holtzman, DM
中科院分区：
文献类型：
--
作者：
Fryer, JD;Simmons, K;Holtzman, DM
阿尔茨海默病（AD）的特征在于正常可溶的淀粉样蛋白-β（A β）肽在脑的细胞外空间中作为实质斑块聚集和沉积，以及在脑血管壁中作为脑淀粉样蛋白血管病（CAA）聚集和沉积。CAA是脑出血的常见原因，见于大多数AD患者。在AD中，载脂蛋白E（apoE）基因（APOE）的等位基因是CAA的危险因素。为了确定人apoE在体内对CAA的影响，我们将人APOE 3和APOE 4“敲入”小鼠培育成转基因小鼠模型（Tg 2576），其发展淀粉样蛋白斑块以及CAA。两种人apoE亚型的表达导致A β沉积相对于鼠apoE延迟数月。Tg 2576小鼠表达更多的原纤维形成的小鼠apoE发展实质淀粉样蛋白斑块和CAA的9个月大。在15月龄时，人apoE 4的表达导致实质性CAA，实质斑块很少，而人apoE 3的表达导致几乎没有CAA或实质斑块。此外，表达apoE 4的年轻小鼠在脑细胞外池中A β 40：42的比例升高，而在CSF中的比例较低，表明apoE 4导致不同脑区室中A β物质的清除和转运改变。这些发现表明，一旦A β纤维形成发生，apoE 4有利于CAA的形成，而不是实质斑块，并表明增加A β 40：42比例的分子或治疗可能有利于CAA的形成，而不是实质斑块。
Alzheimer's disease (AD) is characterized by the aggregation and deposition of the normally soluble amyloid-beta (A beta) peptide in the extracellular spaces of the brain as parenchymal plaques and in the walls of cerebral vessels as cerebral amyloid angiopathy (CAA). CAA is a common cause of brain hemorrhage and is found in most patients with AD. As in AD, the epsilon 4 allele of the apolipoprotein E (apoE) gene (APOE) is a risk factor for CAA. To determine the effect of human apoE on CAA in vivo, we bred human APOE3 and APOE4 "knock-in" mice to a transgenic mouse model (Tg2576) that develops amyloid plaques as well as CAA. The expression of both human apoE isoforms resulted in a delay in A beta deposition of several months relative to murine apoE. Tg2576 mice expressing the more fibrillogenic murine apoE develop parenchymal amyloid plaques and CAA by 9 months of age. At 15 months of age, the expression of human apoE4 led to substantial CAA with very few parenchymal plaques, whereas the expression of human apoE3 resulted in almost no CAA or parenchymal plaques. Additionally, young apoE4-expressing mice had an elevated ratio of A beta 40:42 in brain extracellular pools and a lower 40:42 ratio in CSF, suggesting that apoE4 results in altered clearance and transport of A beta species within different brain compartments. These findings demonstrate that, once A beta fibrillogenesis occurs, apoE4 favors the formation of CAA over parenchymal plaques and suggest that molecules or treatments that increase the ratio of A beta 40:42 may favor the formation of CAA versus parenchymal plaques.