Human Umbilical Cord Blood Serum-derived α-Secretase: Functional Testing in Alzheimer's Disease Mouse Models.
Human Umbilical Cord Blood Serum-derived α-Secretase: Functional Testing in Alzheimer's Disease Mouse Models.
复制标题
DOI：
10.1177/0963689718759473
复制
发表时间：
2018-03
影响因子：
3.3
通讯作者：
Tan J
中科院分区：
文献类型：
--
作者：
Habib A;Hou H;Mori T;Tian J;Zeng J;Fan S;Giunta B;Sanberg PR;Sawmiller D;Tan J
阿尔茨海默病（AD）是一种影响认知的年龄相关性疾病。我们的前期研究表明，淀粉样蛋白促发蛋白（APP）代谢产物可溶性APPα（sAPPα）具有神经保护作用，可干扰β-位点APP裂解酶1（BACE 1，β-secretase）的裂解，减少β淀粉样蛋白（Aβ）的生成。在试图确定恢复sAPPα水平的方法时，我们发现在稳定表达野生型人APP的中国仓鼠卵巢细胞中，与成人血清（ABS）和老年血清（AgBS）相比，人脐带血血清（CBS）显著促进sAPPα的产生。有趣的是，CBS在无细胞系统中选择性介导人神经元特异性重组APP 695的α-分泌酶切割，而不依赖于肿瘤坏死因子-α。α转化酶（TACE;一种含有去整合素和金属蛋白酶结构域的蛋白17 [ADAM 17]）和ADAM。随后，使用3步色谱分离技术（即，二乙氨基乙醇，尺寸排阻和离子交换色谱），我们纯化并最终鉴定了具有增强的α-分泌酶催化活性的CBS特异性级分（称为αCBSF），并发现αCBSF与原始合并CBS相比具有超过3，000倍的α-分泌酶催化活性增加。此外，在三重转基因阿尔茨海默病（3xTg-AD）小鼠中，与具有增强的α-分泌酶活性的AgBS组分（AgBSF）治疗相比，侧脑室注射αCBSF显著增加脑sAPPα水平，同时显著降低脑Aβ产生和异常tau（Thr 231）磷酸化。此外，AgBSF通过渗透微型泵腹膜内给予具有5个家族性阿尔茨海默病突变（5XFAD）的转基因小鼠6周（wk），改善了β-淀粉样蛋白斑块并逆转了认知障碍测量。总之，我们的结果提出了进一步研究的必要性，旨在识别和表征CBS中的α-分泌酶，以获得新的有效的AD治疗。
Alzheimer’s disease (AD) is an age-related disorder that affects cognition. Our previous studies showed that the neuroprotective fragment of amyloid procurer protein (APP) metabolite, soluble APPα (sAPPα), interferes with β-site APP-cleaving enzyme 1 (BACE1, β-secretase) cleavage and reduces amyloid-β (Aβ) generation. In an attempt to identify approaches to restore sAPPα levels, we found that human cord blood serum (CBS) significantly promotes sAPPα production compared with adult blood serum (ABS) and aged blood serum (AgBS) in Chinese hamster ovary cells stably expressing wild-type human APP. Interestingly, CBS selectively mediated the α-secretase cleavage of human neuron-specific recombinant APP695 in a cell-free system independent of tumor necrosis factor-α converting enzyme (TACE; a disintegrin and metalloproteinase domain-containing protein 17 [ADAM17]) and ADAM. Subsequently, using 3-step chromatographic separation techniques (i.e., diethylaminoethanol, size-exclusion, and ion-exchange chromatography), we purified and ultimately identified a CBS-specific fraction with enhanced α-secretase catalytic activity (termed αCBSF) and found that αCBSF has more than 3,000-fold increased α-secretase catalytic activity compared with the original pooled CBS. Furthermore, intracerebroventricular injection of αCBSF markedly increased cerebral sAPPα levels together with significant decreases in cerebral Aβ production and abnormal tau (Thr231) phosphorylation compared with the AgBS fraction with enhanced α-secretase activity (AgBSF) treatment in triple transgenic Alzheimer’s disease (3xTg-AD) mice. Moreover, AgBSF administered intraperitoneally to transgenic mice with five familial Alzheimer’s disease mutations (5XFAD) via an osmotic mini pump for 6 weeks (wk) ameliorated β-amyloid plaques and reversed cognitive impairment measures. Together, our results propose the necessity for further study aimed at identification and characterization of α-secretase in CBS for novel and effective AD therapy.
登录
查看更多内容
影响因子：
4.6
作者：
Castellano JM;Palner M;Li SB;Freeman GM Jr;Nguyen A;Shen B;Stan T;Mosher KI;Chin FT;de Lecea L;Luo J;Wyss-Coray T
通讯作者：
Wyss-Coray T
影响因子：
16.6
作者：
通讯作者：
--
影响因子：
--
作者：
Isozaki, Takeo;Arbab, Ali S.;Haas, Christian S.;Amin, M. Asif;Arendt, Monica D.;Koch, Alisa E.;Ruth, Jeffrey H.
通讯作者：
Ruth, Jeffrey H.
影响因子：
4.8
作者：
Mockett BG;Richter M;Abraham WC;Müller UC
通讯作者：
Müller UC
影响因子：
4.2
作者：
Habib A;Sawmiller D;Tan J
通讯作者：
Tan J