Sortilin Fragments Deposit at Senile Plaques in Human Cerebrum.
Sortilin Fragments Deposit at Senile Plaques in Human Cerebrum.
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分拣蛋白碎片沉积在人类大脑的老年斑块上
DOI：
10.3389/fnana.2017.00045
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发表时间：
2017
影响因子：
2.9
通讯作者：
Yan XX
中科院分区：
文献类型：
--
作者：
Hu X;Hu ZL;Li Z;Ruan CS;Qiu WY;Pan A;Li CQ;Cai Y;Shen L;Chu Y;Tang BS;Cai H;Zhou XF;Ma C;Yan XX
空泡蛋白分类10蛋白(Vps10p)家族的基因变异与阿尔茨海默病(AD)有关。在这里，我们展示了老年和AD人类大脑中Vps10p成员sortilin的片段在老年斑(SP)处的沉积。用抗细胞外和细胞内C-末端结构域的抗体来表征死后大脑中山梨素的变化。这两种抗体在正常人类大脑中的标记相同，出现在皮质和海马神经元的胞体和树突中。C-末端抗体在部分老年人和所有AD患者中也有细胞外病变，表现为孤立的纤维、小斑块、致密堆积或环状成熟斑块。索替林和β-淀粉样蛋白(A-β)沉积在颞叶结构中以区域/板层和病例相关的方式明显相关，在单个SP处可见共同定位的免疫荧光。然而，在软脑膜周围、血管壁或具有典型弥漫性Aβ沉积的区域很少出现山梨素的沉积，加热或甲酸切片预处理不会增强标记物。一个主要的山梨素片段~15 kDa的水平，预计来自C-末端区域，在AD患者中显著高于对照皮质裂解物。因此，山梨素片段是人类大脑SPS细胞外沉积蛋白产物的重要组成部分。
Genetic variations in the vacuolar protein sorting 10 protein (Vps10p) family have been linked to Alzheimer’s disease (AD). Here we demonstrate deposition of fragments from the Vps10p member sortilin at senile plaques (SPs) in aged and AD human cerebrum. Sortilin changes were characterized in postmortem brains with antibodies against the extracellular and intracellular C-terminal domains. The two antibodies exhibited identical labeling in normal human cerebrum, occurring in the somata and dendrites of cortical and hippocampal neurons. The C-terminal antibody also marked extracellular lesions in some aged and all AD cases, appearing as isolated fibrils, mini-plaques, dense-packing or circular mature-looking plaques. Sortilin and β-amyloid (Aβ) deposition were correlated overtly in a region/lamina- and case-dependent manner as analyzed in the temporal lobe structures, with co-localized immunofluorescence seen at individual SPs. However, sortilin deposition rarely occurred around the pia, at vascular wall or in areas with typical diffuse Aβ deposition, with the labeling not enhanced by section pretreatment with heating or formic acid. Levels of a major sortilin fragment ~15 kDa, predicted to derive from the C-terminal region, were dramatically elevated in AD relative to control cortical lysates. Thus, sortilin fragments are a prominent constituent of the extracellularly deposited protein products at SPs in human cerebrum.