Somatostatin receptor subtype-4 agonist NNC 26-9100 decreases extracellular and intracellular Aβ₁₋₄₂ trimers.
Somatostatin receptor subtype-4 agonist NNC 26-9100 decreases extracellular and intracellular Aβ₁₋₄₂ trimers.
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生长抑素受体亚型 4 激动剂 NNC 26-9100 减少细胞外和细胞内 Aβαβ三聚体。
DOI：
10.1016/j.ejphar.2012.03.020
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发表时间：
2012
影响因子：
5
通讯作者：
Witt,KenA
中科院分区：
文献类型：
--
作者：
Sandoval,KarinE;Farr,SusanA;Banks,WilliamA;Crider,AlbertM;Morley,JohnE;Witt,KenA
可溶性淀粉样β蛋白（Aβ）低聚物是与阿尔茨海默病进展相关的突触功能障碍的主要介质。这种Aβ低聚物的存在取决于它们的聚集率和代谢率。选择性生长抑素受体亚型激动剂的使用已被确定为通过调节neprilysin酶来减轻a β在大脑中的积累的潜在手段。在此，我们首先评估了生长抑素受体亚型4激动剂1-[3-[N-（5-溴吡啶-2-基）-N-（3,4-二氯苯基）氨基]丙基]-3-[3-（h -咪唑-4-基）丙基]硫脲（NNC 26-9100）对12月龄SAMP8小鼠（i.c.v.注射）学习和记忆的影响。NNC 26-9100 （0.2μg剂量）对学习（t -迷宫）和记忆（物体识别）均有增强作用。在NNC 26-9100 （0.2μg）或给药后，评估皮质和海马组织中neprilysin活性的变化，以及淀粉样前体蛋白（APP）、neprilysin和a - β1 - 42低聚物在各自细胞组分（细胞外、细胞内和膜）中的蛋白表达。NNC 26-9100增加了皮质组织中neprilysin的活性，细胞外部分的相关蛋白表达增加，细胞内部分的相关蛋白表达减少。在皮质和海马组织治疗后发现细胞内APP表达减少。NNC 26-9100也显著降低了细胞外和细胞内皮质部分a β1 - 42三聚体的表达。在膜组分中未发现任何蛋白的表达变化。这些发现表明，选择性SSTR4激动剂可能用于减轻与学习和记忆衰退有关的大脑关键区域中a β1 - 42的毒性寡聚形式。
Soluble amyloid β-protein (Aβ) oligomers are primary mediators of synaptic dysfunction associated with the progression of Alzheimer's disease. Such Aβ oligomers exist dependent on their rates of aggregation and metabolism. Use of selective somatostatin receptor-subtype agonists have been identified as a potential means to mitigate Aβ accumulation in the brain, via regulation of the enzyme neprilysin. Herein, we first evaluated the impact of the somatostatin receptor subtype-4 agonist 1-[3-[N-(5-Bromopyridin-2-yl)-N-(3,4-dichlorobenzyl)amino]propyl]-3-[3-(1H-imidazol-4-yl)propyl]thiourea (NNC 26–9100) on learning and memory in 12-month SAMP8 mice (i.c.v. injection). NNC 26–9100 (0.2μg-dose) was shown to enhance both learning (T-maze) and memory (object recognition) compared to vehicle controls. Cortical and hippocampal tissues were evaluated subsequent to NNC 26–9100 (0.2μg) or vehicle administration for changes in neprilysin activity, along with protein expression of amyloid-precursor protein (APP), neprilysin, and Aβ1–42oligomers within respective cellular fractions (extracellular, intracellular and membrane). NNC 26–9100 increased neprilysin activity in cortical tissue, with an associated protein expression increase in the extracellular fraction and decreased in the intracellular fraction. A decrease in intracellular APP expression was found with treatment in both cortical and hippocampal tissues. NNC 26–9100 also significantly decreased expression of Aβ1–42trimers within both the extracellular and intracellular cortical fractions. No expression changes were found in membrane fractions for any protein. These finding suggest the potential use of selective SSTR4 agonists to mitigate toxic oligomeric forms of Aβ1–42in critical regions of the brain identified with learning and memory decline.