Geriatric Research, Education and Clinical Center (GRECC), St Louis Veterans Affairs Medical Center, St Louis, MO, USA; Division of Geriatric Medicine, Saint Louis University School of Medicine, St Louis, MO, USA; Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St Louis, MO, USA.
Neurobiol Aging. 2014 Jan;35(1):159-68. doi: 10.1016/j.neurobiolaging.2013.07.018. Epub 2013 Aug 19.
The senescence-accelerated mouse (SAMP8) strain exhibits decreased learning and memory and increased amyloid beta (Aβ) peptide 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- 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 (6 genes), phosphatidylinositol signaling (6 genes), and endocytosis (10 genes) pathways. The changes in long term potentiation included mitogen-activated protein kinase (MAPK) signaling (N-ras, cAMP responsive element binding protein [CREB], protein phosphatase inhibitor 1) and Ca-dependent signaling (inositol triphosphate [ITP] receptors 1 and 2 and phospholipase C). Changes in phosphatidylinositol signaling genes suggested altered signaling through phosphatidylinositol-3-kinase, and Western blotting revealed phosphorylation changes in serine/threonine protein kinase 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 gene expression in 3 SAMP8 hippocampal pathways associated with memory formation and consolidation. These pathways might provide new therapeutic targets in addition to targeting Aβ metabolism itself.
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，以及淀粉样β（Aβ）肽积累增加。为了检测 SAMP8 小鼠基因表达的差异，我们使用了一种 50%由 SAMP8 和 CD-1 小鼠杂交的对照小鼠，该小鼠没有记忆缺陷（50% SAMs）。然后，我们使用 Affymetrix 基因芯片比较了 4 个月和 12 个月大的 SAMP8 和对照小鼠海马体的基因表达。在 12 个月时，但不是在 4 个月时，通路分析显示长时程增强（6 个基因）、磷脂酰肌醇信号（6 个基因）和内吞作用（10 个基因）通路存在显著差异。长时程增强的变化包括丝裂原激活蛋白激酶（MAPK）信号（N-ras、cAMP 反应元件结合蛋白[CREB]、蛋白磷酸酶抑制剂 1）和 Ca 依赖性信号（三磷酸肌醇[ITP]受体 1 和 2 和磷脂酶 C）。磷脂酰肌醇信号基因的变化表明磷脂酰肌醇-3-激酶信号发生改变，Western blot 显示丝氨酸/苏氨酸蛋白激酶 AKT 和 70S6K 的磷酸化变化。内吞作用途径的变化涉及与网格蛋白介导的内吞作用（动力蛋白和网格蛋白）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。总之，这些研究表明，3 种与记忆形成和巩固相关的 SAMP8 海马途径的基因表达发生改变。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。
