Armbrecht Harvey J, Siddiqui Akbar M, Green Michael, Farr Susan A, Kumar Vijaya B, Banks William A, Patrick Ping, Shah Gul N, Morley John E
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.
J Alzheimers Dis. 2015;46(2):535-48. doi: 10.3233/JAD-142760.
The senescence-accelerated mouse (SAMP8) strain exhibits an age-related decrease in memory accompanied by an increase in hippocampal amyloid-β protein precursor (AβPP) and amyloid-β peptide (Aβ). We have shown that administration of an antisense oligonucleotide against the Aβ region of AβPP (AβPP antisense) reverses the memory deficits. The purpose of this study was to determine the effect of peripheral (IV) administration of AβPP antisense on hippocampal gene expression. The AβPP antisense reversed the memory deficits and altered expression of 944 hippocampal genes. Pathway analysis showed significant gene expression changes in nine pathways. These include the MAPK signaling pathway (p = 0.0078) and the phosphatidylinositol signaling pathway (p = 0.043), which we have previously shown to be altered in SAMP8 mice. The changes in these pathways contributed to significant changes in the neurotropin (p = 0.0083) and insulin signaling (p = 0.015) pathways, which are known to be important in learning and memory. Changes in these pathways were accompanied by phosphorylation changes in the downstream target proteins p70S6K, GSK3β, ERK, and CREB. These changes in hippocampal gene expression and protein phosphorylation may suggest specific new targets for antisense therapy aimed at improving memory.
衰老加速小鼠（SAMP8）品系表现出与年龄相关的记忆减退，同时海马淀粉样β蛋白前体（AβPP）和淀粉样β肽（Aβ）增加。我们已经表明，给予针对AβPP的Aβ区域的反义寡核苷酸（AβPP反义）可逆转记忆缺陷。本研究的目的是确定外周（静脉内）给予AβPP反义对海马基因表达的影响。AβPP反义逆转了记忆缺陷并改变了944个海马基因的表达。通路分析显示九个通路中有显著的基因表达变化。这些包括丝裂原活化蛋白激酶信号通路（p = 0.0078）和磷脂酰肌醇信号通路（p = 0.043），我们之前已表明这些通路在SAMP8小鼠中发生了改变。这些通路的变化导致神经营养因子（p = 0.0083）和胰岛素信号通路（p = 0.015）发生显著变化，已知这些通路在学习和记忆中很重要。这些通路的变化伴随着下游靶蛋白p70S6K、GSK3β、ERK和CREB的磷酸化变化。海马基因表达和蛋白质磷酸化的这些变化可能为旨在改善记忆的反义治疗提示特定的新靶点。
