Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes
Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes
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DOI：
10.1073/pnas.1609896113
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发表时间：
2016-09-06
影响因子：
11.1
通讯作者：
Barres, Ben A.
中科院分区：
文献类型：
--
作者：
Chung, Won-Suk;Verghese, Philip B.;Barres, Ben A.
影响迟发性阿尔茨海默病（AD）易感性的最强遗传危险因素是载脂蛋白E（APOE）基因型。APOE在人类中有三种常见的同种型，E2，E3和E4。E4等位基因的两个拷贝的存在使AD的风险增加12倍，而E2等位基因与AD的风险降低两倍相关。这些数据将APOE置于AD病理生理学的中心，但目前尚不清楚APOE等位基因如何改变AD风险。最近，我们发现星形胶质细胞，一个主要的中枢神经系统细胞类型，产生APOE，是高度吞噬和参与正常的突触修剪和营业额。在这里，我们报告了一个新的作用，APOE在控制吞噬能力的星形胶质细胞是高度依赖于APOE亚型。APOE 2增强星形胶质细胞对突触的吞噬率，而APO 4降低吞噬率。我们还发现，海马中C1q蛋白的积累量高度依赖于APOE等位基因，这可能代表衰老突触的积累，增强了对补体介导的变性的脆弱性：与APOE3 KI动物相比，APOE2基因敲入（KI）动物的C1q蓄积显著降低，APOE4 KI动物的C1q蓄积显著增加。这些研究揭示了APOE在调节星形胶质细胞突触修剪速率中的一种新的等位基因依赖性作用。他们还提出了这样的假设，即APOE4的AD易感性可能部分源于星形胶质细胞的吞噬能力缺陷，其加速了C1q包被的衰老突触的积累速率，增强了突触对经典补体级联介导的神经变性的脆弱性。
The strongest genetic risk factor influencing susceptibility to lateonset Alzheimer's disease (AD) is apolipoprotein E (APOE) genotype. APOE has three common isoforms in humans, E2, E3, and E4. The presence of two copies of the E4 allele increases risk by similar to 12-fold whereas E2 allele is associated with an similar to twofold decreased risk for AD. These data put APOE central to AD pathophysiology, but it is not yet clear how APOE alleles modify AD risk. Recently we found that astrocytes, a major central nervous system cell type that produces APOE, are highly phagocytic and participate in normal synapse pruning and turnover. Here, we report a novel role for APOE in controlling the phagocytic capacity of astrocytes that is highly dependent on APOE isoform. APOE2 enhances the rate of phagocytosis of synapses by astrocytes, whereas APO4 decreases it. We also found that the amount of C1q protein accumulation in hippocampus, which may represent the accumulation of senescent synapses with enhanced vulnerability to complement-mediated degeneration, is highly dependent on APOE alleles: C1q accumulation was significantly reduced in APOE2 knock-in (KI) animals and was significantly increased in APOE4 KI animals compared with APOE3 KI animals. These studies reveal a novel allele-dependent role for APOE in regulating the rate of synapse pruning by astrocytes. They also suggest the hypothesis that AD susceptibility of APOE4 may originate in part from defective phagocytic capacity of astrocytes which accelerates the rate of accumulation of C1q-coated senescent synapses, enhancing synaptic vulnerability to classical-complement-cascade mediated neurodegeneration.