BACE2 distribution in major brain cell types and identification of novel substrates.
BACE2 distribution in major brain cell types and identification of novel substrates.
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DOI：
10.26508/lsa.201800026
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发表时间：
2018-01
影响因子：
4.4
通讯作者：
De Strooper B
中科院分区：
文献类型：
--
作者：
Voytyuk I;Mueller SA;Herber J;Snellinx A;Moechars D;van Loo G;Lichtenthaler SF;De Strooper B
抑制β-Site app - cleaved enzyme 1 （BACE1）治疗阿尔茨海默病同时也抑制BACE2。这项工作显示了BACE2在小鼠大脑中的表达，并鉴定了其底物。在炎症条件下，血管细胞粘附分子1的BACE2加工增加，对目前在临床中使用非特异性BACE1抑制剂提出了警告。β-Site app - cleaved enzyme 1 （BACE1）抑制被认为是阿尔茨海默病最有前途的治疗策略之一，但目前的BACE1抑制剂也会阻断BACE2。由于BACE2在大脑中的定位和功能尚不清楚，因此很难预测BACE2的脱靶抑制是否会引起相关副作用，以及产生bace1特异性抑制剂是否重要。在这里，我们发现BACE2在成年小鼠大脑的神经元和胶质细胞的离散亚群中表达。我们在培养的胶质细胞中发现了四种新的由BACE2加工的底物：血管细胞粘附分子1、三角洲和缺口样表皮生长因子相关受体、成纤维细胞生长因子受体1和丛蛋白结构域2。尽管这些底物在健康成年小鼠中没有被BACE2显著切割，但促炎TNF诱导BACE2介导的脑脊液中血管细胞粘附分子1的脱落急剧增加。因此，尽管在稳态条件下，bace1定向抑制剂对BACE2交叉抑制的作用相当微妙，但重要的是要考虑到，在诱导TNF表达的生理病理条件下，副作用可能会变得明显。
β-Site APP-cleaving enzyme 1 (BACE1) inhibition to treat Alzheimer’s disease also inhibits BACE2. This work shows BACE2 expression in the mouse brain and identifies its substrates. Increased BACE2 processing of vascular cell adhesion molecule 1 during inflammatory conditions cautions the use of current nonspecific BACE1 inhibitors in the clinic. β-Site APP-cleaving enzyme 1 (BACE1) inhibition is considered one of the most promising therapeutic strategies for Alzheimer’s disease, but current BACE1 inhibitors also block BACE2. As the localization and function of BACE2 in the brain remain unknown, it is difficult to predict whether relevant side effects can be caused by off-target inhibition of BACE2 and whether it is important to generate BACE1-specific inhibitors. Here, we show that BACE2 is expressed in discrete subsets of neurons and glia throughout the adult mouse brain. We uncover four new substrates processed by BACE2 in cultured glia: vascular cell adhesion molecule 1, delta and notch-like epidermal growth factor–related receptor, fibroblast growth factor receptor 1, and plexin domain containing 2. Although these substrates were not prominently cleaved by BACE2 in healthy adult mice, proinflammatory TNF induced a drastic increase in BACE2-mediated shedding of vascular cell adhesion molecule 1 in CSF. Thus, although under steady-state conditions the effect of BACE2 cross-inhibition by BACE1-directed inhibitors is rather subtle, it is important to consider that side effects might become apparent under physiopathological conditions that induce TNF expression.
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VCAM-1和ICAM-1与粘附白细胞的新型内皮对接结构中的动态相互作用。
DOI：
10.1083/jcb.200112126
发表时间：
2002-06-24
期刊：
The Journal of cell biology
影响因子：
--
作者：
Barreiro O;Yanez-Mo M;Serrador JM;Montoya MC;Vicente-Manzanares M;Tejedor R;Furthmayr H;Sanchez-Madrid F
通讯作者：
Sanchez-Madrid F
影响因子：
8
作者：
Alcarraz-Vizan, Gema;Castano, Carlos;Novials, Anna
通讯作者：
Novials, Anna
影响因子：
4.8
作者：
Bennett, BD;Babu-Khan, S;Vassar, R
通讯作者：
Vassar, R
影响因子：
64.8
作者：
De Strooper, B;Saftig, P;Van Leuven, F
通讯作者：
Van Leuven, F
影响因子：
3.3
作者：
Hasan, Mahbub;Seo, Ji-Eun;Kwon, Oh-Seung
通讯作者：
Kwon, Oh-Seung