SAMP8 mice have altered hippocampal gene expression in long term potentiation, phosphatidylinositol signaling, and endocytosis pathways.
SAMP8 mice have altered hippocampal gene expression in long term potentiation, phosphatidylinositol signaling, and endocytosis pathways.
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DOI：
10.1016/j.neurobiolaging.2013.07.018
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发表时间：
2014-01
影响因子：
4.2
通讯作者：
Morley JE
中科院分区：
文献类型：
--
作者：
Armbrecht HJ;Siddiqui AM;Green M;Farr SA;Kumar VB;Banks WA;Patrick P;Shah GN;Morley JE
衰老加速小鼠(SAMP8)品系在12个月时表现出学习和记忆能力下降，淀粉样β蛋白(Aβ)积累增加。为了检测SAMP8小鼠基因表达的差异，我们使用了一只对照小鼠，它是SAMP8和CD-1小鼠的50%杂交，并且没有表现出记忆缺陷(50%SAM)。然后，我们使用Affymetrix基因阵列比较了4个月和12个月大的SAMP8和对照组小鼠海马区的基因表达。在12个月时，而不是在4个月时，通路分析显示长期增强(LTP)(6个基因)、磷脂酰肌醇信号通路(6个基因)和内吞作用(10个基因)通路有显著差异。LTP的变化包括MAPK信号(N-ras、CREB结合蛋白、蛋白磷酸酶抑制物1)和钙依赖信号(ITP受体1、2和磷脂酶C)。磷脂酰肌醇信号转导基因的改变提示通过PI3-激酶的信号转导发生改变，Western blotting显示AKT和70S6K的磷酸化改变。内吞作用途径的改变涉及与网状蛋白介导的内吞作用(动力素和网状蛋白)相关的基因。内吞作用是受体循环所必需的，参与Aβ代谢，并受磷脂酰肌醇信号调节。综上所述，这些研究表明，与记忆形成和巩固相关的三条SAMP8海马区通路中的基因表达发生了变化。这些途径除了靶向Aβ代谢本身外，还可能提供新的治疗靶点。
The senescence-accelerated mouse (SAMP8) strain exhibits decreased learning and memory and increased amyloid beta peptide (Aβ) accumulation at 12 months. To detect differences in gene expression in SAMP8 mice, we used a Control mouse that was a 50% cross between SAMP8 and CD-1 mice and which showed no memory deficits (50% SAMs). We then compared gene expression in the hippocampus of 4 month and 12 month old SAMP8 and Control mice using Affymetrix gene arrays. At 12 months, but not at 4 months, pathway analysis revealed significant differences in the Long Term Potentiation (LTP) (6 genes), Phosphatidylinositol Signaling (6 genes), and Endocytosis (10 genes) pathways. The changes in LTP included MAPK signaling (N-ras, CREB binding protein, protein phosphatase inhibitor 1) and Ca-dependent signaling (ITP receptors 1 and 2 and phospholipase C). Changes in phosphatidylinositol signaling genes suggested altered signaling through PI3-kinase, and Western blotting revealed phosphorylation changes in AKT and 70S6K. Changes in the Endocytosis pathway involved genes related to clathrin-mediated endocytosis (dynamin and clathrin). Endocytosis is required for receptor recycling, is involved in Aβ metabolism, and is regulated by phosphatidylinositol signaling. In summary, these studies demonstrate altered genes expression in three SAMP8 hippocampal pathways associated with memory formation and consolidation. These pathways may provide new therapeutic targets in addition to targeting Aβ metabolism itself.
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