Apolipoprotein A-I Deficiency Increases Cerebral Amyloid Angiopathy and Cognitive Deficits in APP/PS1ΔE9 Mice
Apolipoprotein A-I Deficiency Increases Cerebral Amyloid Angiopathy and Cognitive Deficits in APP/PS1ΔE9 Mice
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DOI：
10.1074/jbc.m110.127738
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发表时间：
2010-11-19
影响因子：
4.8
通讯作者：
Koldamova, Radosveta
中科院分区：
文献类型：
--
作者：
Lefterov, Iliya;Fitz, Nicholas F.;Koldamova, Radosveta
阿尔茨海默病（AD）的一个标志是淀粉样β蛋白（Aβ）在脑实质和脑血管中沉积，并伴有认知能力下降。此前，我们发现人载脂蛋白A - I（apoA - I）可减少Aβ（40）的聚集和毒性。在此我们证明，脂质化或非脂质化形式的apoA - I可阻止Aβ（42）高分子量聚集体的形成，并降低Aβ（42）对原代脑细胞的毒性。为了确定apoA - I在体内对AD表型的影响，我们将APP/PS1ΔE9小鼠与apoA - I基因敲除（apoA - I - KO）小鼠进行杂交。通过莫里斯水迷宫实验，我们证明小鼠Apoa - I的缺失会加剧APP/PS1ΔE9小鼠的记忆缺陷。对APP/PS1ΔE9/apoA - I - KO小鼠的进一步特征分析表明，apoA - I缺乏并不影响淀粉样前体蛋白的加工、可溶性Aβ寡聚体水平、Aβ斑块负荷或脑实质中不溶性Aβ的水平。为了检测Apoa - I缺失对脑淀粉样血管病的影响，我们测量了从脑血管中分离出的不溶性Aβ。我们的数据显示，在APP/PS1ΔE9/apoA - I - KO小鼠中，不溶性Aβ（40）增加了10倍以上，Aβ（42）增加了1.5倍。通过X - 34染色测量，APP/PS1ΔE9/apoA - I - KO小鼠皮质和海马血管中沉积的淀粉样蛋白水平升高，证实了上述结果。最后，我们证明脂质化和非脂质化的apoA - I可显著降低Aβ对脑血管平滑肌细胞的毒性。我们得出结论，apoA - I的缺乏会加剧APP/PS1ΔE9小鼠的记忆缺陷，同时显著加重脑淀粉样血管病。
A hallmark of Alzheimer disease (AD) is the deposition of amyloid beta (A beta) in brain parenchyma and cerebral blood vessels, accompanied by cognitive decline. Previously, we showed that human apolipoprotein A-I (apoA-I) decreases A beta(40) aggregation and toxicity. Here we demonstrate that apoA-I in lipidated or non-lipidated form prevents the formation of high molecular weight aggregates of A beta(42) and decreases A beta(42) toxicity in primary brain cells. To determine the effects of apoA-I on AD phenotype in vivo, we crossed APP/PS1 Delta E9 to apoA-I-KO mice. Using a Morris water maze, we demonstrate that the deletion of mouse Apoa-I exacerbates memory deficits in APP/PS1 Delta E9 mice. Further characterization of APP/PS1 Delta E9/apoA-I-KO mice showed that apoA-I deficiency did not affect amyloid precursor protein processing, soluble A beta oligomer levels, A beta plaque load, or levels of insoluble A beta in brain parenchyma. To examine the effect of Apoa-I deletion on cerebral amyloid angiopathy, we measured insoluble A beta isolated from cerebral blood vessels. Our data show that in APP/PS1 Delta E9/apoA-I-KO mice, insoluble A beta(40) is increased more than 10-fold, and A beta(42) is increased 1.5-fold. The increased levels of deposited amyloid in the vessels of cortices and hippocampi of APP/PS1 Delta E9/apoA-I-KO mice, measured by X-34 staining, confirmed the results. Finally, we demonstrate that lipidated and non-lipidated apoA-I significantly decreased A beta toxicity against brain vascular smooth muscle cells. We conclude that lack of apoA-I aggravates the memory deficits in APP/PS1 Delta E9 mice in parallel to significantly increased cerebral amyloid angiopathy.