Proteolytic Cleavage of Apolipoprotein E in the Down Syndrome Brain.
Proteolytic Cleavage of Apolipoprotein E in the Down Syndrome Brain.
复制标题
DOI：
10.14336/ad.2015.1020
复制
发表时间：
2016-05
影响因子：
7.4
通讯作者：
Rohn TT
中科院分区：
文献类型：
--
作者：
Day RJ;McCarty KL;Ockerse KE;Head E;Rohn TT
唐氏综合征（DS）是智力残疾最常见的遗传原因之一，其特征在于许多行为和认知症状。早发性阿尔茨海默病（AD）的许多神经病理学特征，包括老年斑和神经纤维缠结（NFT），也存在于DS患者中，这是21号染色体上淀粉样前体基因三倍化的结果。有证据表明，携带一个或两个载脂蛋白E4（APOE 4）等位基因可能会增加AD的风险，这是由于apoE 4的蛋白水解切割和随后的功能丧失。为了研究apoE蛋白水解在体内的作用，我们比较了三个尸检组; 7个DS与AD神经病理学病例超过40岁，5个年轻的DS病例没有AD病理学40岁以下（YDS）和5个年龄匹配的对照病例超过40岁，通过免疫组化利用抗体检测apoE的氨基末端片段。这种抗体的应用，称为氨基末端载脂蛋白E片段抗体（nApoECF）显示标记的锥体神经元在额叶皮质的YDS的情况下，而在DS-AD组，标记与nApoECF是突出的NFT。在相同的DS-AD病例中，海马中nApoECF的NFT标记显著高于额叶皮质，表明截短的apoE存在区域分布。共定位免疫荧光实验表明，52.5%和53.2%的AT 8-和PHF-1-阳性NFT，分别也含有nApoECF。总的来说，这些数据支持了DS中apoE蛋白水解裂解的作用，并表明apoE片段化与NFT密切相关。
Down syndrome (DS) is one of the most common genetic causes of intellectual disability and is characterized by a number of behavioral as well as cognitive symptoms. Many of the neuropathological features of early-onset Alzheimer’s disease (AD) including senile plaques and neurofibrillary tangles (NFTs) are also present in people with DS as a result of triplication of the amyloid precursor gene on chromosome 21. Evidence suggests that harboring one or both apolipoprotein E4 (APOE4) alleles may increase the risk for AD due to the proteolytic cleavage of apoE4 and a subsequent loss of function. To investigate a role for the apoE proteolysis in vivo, we compared three autopsy groups; 7 DS with AD neuropathology cases over 40 years, 5 young DS cases without AD pathology under 40 years (YDS) and 5 age-matched control cases over 40 years by immunohistochemistry utilizing an antibody that detects the amino-terminal fragment of apoE. Application of this antibody, termed the amino-terminal apoE fragment antibody (nApoECF) revealed labeling of pyramidal neurons in the frontal cortex of YDS cases, whereas in the DS-AD group, labeling with nApoECF was prominent within NFTs. NFT labeling with nApoECF was significantly greater in the hippocampus versus the frontal cortex in the same DS-AD cases, suggesting a regional distribution of truncated apoE. Colocalization immunofluorescence experiments indicated that 52.5% and 53.2% of AT8- and PHF-1-positive NFTs, respectively, also contained nApoECF. Collectively, these data support a role for the proteolytic cleavage of apoE in DS and suggest that apoE fragmentation is closely associated with NFTs.