Somatostatin receptor subtype-4 agonist NNC 26-9100 mitigates the effect of soluble Aβ(42) oligomers via a metalloproteinase-dependent mechanism.
Somatostatin receptor subtype-4 agonist NNC 26-9100 mitigates the effect of soluble Aβ(42) oligomers via a metalloproteinase-dependent mechanism.
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DOI：
10.1016/j.brainres.2013.05.006
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发表时间：
2013-07-03
期刊：
影响因子：
2.9
通讯作者：
Witt KA
中科院分区：
文献类型：
--
作者：
Sandoval KE;Farr SA;Banks WA;Crider AM;Morley JE;Witt KA
可溶性淀粉样β肽（A β）寡聚体被假设为阿尔茨海默病进展的主要介质。在这方面，脑内可溶性A β-寡聚体水平的降低可能提供治疗该疾病的可行方法。已提出生长抑素受体亚型-4（SSTR 4）激动剂通过增强酶降解来降低脑中的A β水平。在本文中，我们使用衰老加速小鼠prone-8（SAMP 8）模型，评价了选择性SSTR 4激动剂NNC 26 - 9100在与M13-金属蛋白酶家族酶抑制剂phosphoramidon联合给药和不联合给药的情况下对学习和可溶性A β 42寡聚体脑含量变化的影响。NNC 26 - 9100处理（2 μ L中0.2 μ g i.c.v.）改善了学习，这被phosphoramidon（分别为1和10 mM）阻断。NNC 26 - 9100可降低总可溶性A β 42，该作用可被phosphoramidon（10 mM）阻断。然后从皮质组织中分离细胞外、细胞内和膜组分，并评估可溶性寡聚体的变化。NNC 26 - 9100减少了细胞外和细胞内组分中的A β 42三聚体（12 kDa）形式，并在细胞外组分中产生了A β 42六聚体（25 kDa）形式的条带分裂效应。这些作用也被磷氨酮（分别为1和10 mM）阻断。随后在APPswe Tg2576转基因小鼠中对NNC 26 - 9100进行的评价显示出相似的学习改善以及细胞外、细胞内和膜组分中可溶性A β 42寡聚体的相应减少。这些数据支持NNC 26 - 9100通过磷酰胺敏感性金属蛋白酶依赖性机制减少可溶性A β 42寡聚体并增强学习的假设。
Soluble amyloid-β peptide (Aβ) oligomers have been hypothesized to be primary mediators of Alzheimer’s disease progression. In this regard, reduction of soluble Aβ-oligomers levels within the brain may provide a viable means in which to treat the disease. Somatostatin receptor subtype-4 (SSTR4) agonists have been proposed to reduce Aβ levels in the brain via enhancement of enzymatic degradation. Herein we evaluated the effect of selective SSTR4 agonist NNC 26-9100 on the changes in learning and soluble Aβ42 oligomer brain content with and without co administration of the M13-metalloproteinase family enzyme-inhibitor phosphoramidon, using the senescence-accelerated mouse prone-8 (SAMP8) model. NNC 26-9100 treatment (0.2 μg i.c.v. in 2 μL) improved learning, which was blocked by phosphoramidon (1 and 10 mM, respectively). NNC 26-9100 decreased total soluble Aβ42, an effect which was blocked by phosphoramidon (10 mM). Extracellular, intracellular, and membrane fractions were then isolated from cortical tissue and assessed for soluble oligomer alterations. NNC 26-9100 decreased the Aβ42 trimeric (12 kDa) form within the extracellular and intracellular fractions, and produced a band-split effect of the Aβ42 hexameric (25 kDa) form within the extracellular fraction. These effects were also blocked by phosphoramdon (1 and 10 mM, respectively). Subsequent evaluation of NNC 26-9100 in APPswe Tg2576 transgenic mice showed a similar learning improvement and corresponding reduction in soluble Aβ42 oligomers within extracellular, intracellular, and membrane fractions. These data support the hypothesis that NNC 26-9100 reduces soluble Aβ42 oligomers and enhances learning through a phosphoramidon-sensitive metalloproteinase-dependent mechanism.
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影响因子：
14
作者：
通讯作者：
--
影响因子：
8.2
作者：
Gimenez-Llort, L.;Blazquez, G.;Fernandez-Teruel, A.
通讯作者：
Fernandez-Teruel, A.
影响因子：
6
作者：
Casas, C;Sergeant, N;Pradier, L
通讯作者：
Pradier, L
DOI：
10.1073/pnas.89.23.11151
发表时间：
1992-12-01
影响因子：
11.1
作者：
BRUNO, JF;XU, Y;BERELOWITZ, M
通讯作者：
BERELOWITZ, M
影响因子：
15
作者：
Ankersen, M;Crider, M;Stidsen, C
通讯作者：
Stidsen, C