Human APOE Isoform-Dependent Effects on Brain β-Amyloid Levels in PDAPP Transgenic Mice
Human APOE Isoform-Dependent Effects on Brain β-Amyloid Levels in PDAPP Transgenic Mice
复制标题
DOI：
10.1523/jneurosci.0887-09.2009
复制
发表时间：
2009-05-27
影响因子：
5.3
通讯作者：
Paul, Steven M.
中科院分区：
文献类型：
--
作者：
Bales, Kelly R.;Liu, Feng;Paul, Steven M.
为了研究人载脂蛋白E（apoE）在体内Aβ沉积中的作用，我们将缺乏小鼠Apoe的PDAPP小鼠与表达人apoE的靶向替换小鼠（PDAPP/TRE2、PDAPP/TRE3或PDAPP/TRE4）进行杂交。然后我们测量了这些不同年龄小鼠的血浆、脑脊液和脑匀浆中apoE蛋白和Aβ肽的水平。我们还对18个月大的小鼠脑内Aβ和淀粉样蛋白负荷量进行了定量。在脑Aβ沉积之前的年龄进行分析的年轻PDAPP/TRE4小鼠中，我们观察到与表达人E2或E3的同龄小鼠相比，其脑脊液和脑中apoE水平显著降低。即使在这个非常早期的时间点，PDAPP/TRE4小鼠脑内Aβ42的水平也大幅升高。在年龄较大的PDAPP/TRE4小鼠中，不溶性apoE蛋白水平随着脑Aβ负荷的急剧增加而平行升高，并且大部分apoE与Aβ相关。在仅TRE4小鼠中，我们还观察到脑匀浆中apoE水平显著降低。由于PDAPP/TRE和仅TRE小鼠中apoE mRNA的相对水平相当，似乎翻译后机制影响了脑内apoE蛋白水平（E4 < E3 > E3 > E2），且该水平随年龄增长而升高。旨在提高apoE蛋白可溶性水平的治疗策略，无论其异构体如何，都可能有效预防和（或）治疗阿尔茨海默病。
To investigate the role of human apolipoprotein E (apoE) on A beta deposition in vivo, we crossed PDAPP mice lacking mouse Apoe to targeted replacement mice expressing human apoE (PDAPP/TRE2, PDAPP/TRE3, or PDAPP/TRE4). We then measured the levels of apoE protein and A beta peptides in plasma, CSF, and brain homogenates in these mice at different ages. We also quantified the amount of brain A beta and amyloid burden in 18-month-old mice. In young PDAPP/TRE4 mice that were analyzed at an age before brain A beta deposition, we observed a significant decrease in the levels of apoE in CSF and brain when compared with age-matched mice expressing either human E2 or E3. The brain levels of A beta 42 in PDAPP/TRE4 mice were substantially elevated even at this very early time point. In older PDAPP/TRE4 mice, the levels of insoluble apoE protein increased in parallel to the dramatic rise in brain A beta burden, and the majority of apoE was associated with A beta. In TRE4 only mice, we also observed a significant decrease in the level of apoE in brain homogenates. Since the relative level of apoE mRNA was equivalent in PDAPP/TRE and TRE only mice, it appears that post-translational mechanisms influence the levels of apoE protein in brain (E4 < E3 > E3 > E2) that increase with age. Therapeutic strategies aimed at increasing the soluble levels of apoE protein, regardless of isoform, may effectively prevent and (or) treat Alzheimer's disease.