Integrative transcriptome profiling of cognitive aging and its preservation through Ser/Thr protein phosphatase regulation

Environmental enrichment has been reported to delay or restore age-related cognitive deficits, however, a mechanism to account for the cause and progression of normal cognitive decline and its preservation by environmental enrichment is lacking. Using genome-wide SAGE-Seq, we provide a global assessment of differentially expressed genes altered with age and environmental enrichment in the hippocampus. Qualitative and quantitative proteomics in naïve young and aged mice was used to further identify phosphorylated proteins differentially expressed with age. We found that increased expression of endogenous protein phosphatase-1 inhibitors in aged mice may be characteristic of long-term environmental enrichment and improved cognitive status. As such, hippocampus-dependent performances in spatial, recognition, and associative memories, which are sensitive to aging, were preserved by environmental enrichment and accompanied by decreased protein phosphatase activity. Age-associated phosphorylated proteins were also found to correspond to the functional categories of age-associated genes identified through transcriptome analysis. Together, this study provides a comprehensive map of the transcriptome and proteome in the aging brain, and elucidates endogenous protein phosphatase-1 inhibition as a potential means through which environmental enrichment may ameliorate age-related cognitive deficits. 4 groups with 3 biological replicates per group: aged in environmental enrichment (EA), aged in standard housing (SA), young in environmental enrichment (EY), and young in standard housing (SY).已有研究表明，环境丰富化（environmental enrichment）可延缓甚至逆转年龄相关的认知功能缺损，但目前仍缺乏能够阐释正常认知衰退的成因与进展、以及环境丰富化发挥保护作用的相关机制。本研究采用全基因组SAGE-Seq技术，对海马体中随年龄与环境丰富化发生改变的差异表达基因开展了全景式分析。通过对未经过实验干预的年轻与衰老小鼠进行定性与定量蛋白质组学分析，本研究进一步筛选出随年龄表达差异的磷酸化蛋白质。研究发现，衰老小鼠体内内源性蛋白磷酸酶1（protein phosphatase-1）抑制剂的表达上调，或可作为长期环境丰富化与认知功能改善的标志性特征。因此，对衰老敏感的海马体依赖型空间记忆、识别记忆与联合记忆功能，可通过环境丰富化得到保留，同时伴随蛋白磷酸酶活性的降低。研究还发现，与衰老相关的磷酸化蛋白质，其功能类别与转录组分析中鉴定出的衰老相关基因的功能类别相一致。综上，本研究绘制了衰老大脑中转录组与蛋白质组的全景图谱，并阐明内源性蛋白磷酸酶1抑制作用或是环境丰富化改善年龄相关认知缺损的潜在途径。本研究共设置4组实验，每组包含3个生物学重复：环境丰富化饲养的衰老小鼠（EA）、标准笼养的衰老小鼠（SA）、环境丰富化饲养的年轻小鼠（EY）以及标准笼养的年轻小鼠（SY）。