Investigating the roles of endogenous APP family members in stress signaling and aging

我们实验室以前的研究表明，APPsα是通过α-分泌酶沿着分泌途径的活性切割APP产生的，通过调节基因表达以及拮抗氧化应激和其他类型的神经毒性应激刺激，从而抑制应激触发的细胞死亡，从而发挥有效的神经保护作用。我们还表明，内源性APP的生物化学加工在非转化的人成纤维细胞老化过程中下调，导致APP α的分泌明显减少。基于这些观察结果，我们的目标是1）进一步研究APP和APLPs及其裂解产物在神经保护中的潜在生理作用，2）分析APP/APLP缺失对基因表达和细胞对神经毒性应激的脆弱性的功能后果，以及3）剖析APP加工在神经元和脑老化过程中的作用及其与年龄相关的应激信号通路的联系，基因表达的改变和氧化变化。

Previous studies from our labs suggest that APPsα, which is generated via cleavage of APP by the activity of α-secretase along the secretory pathway exerts potent neuroprotective effects via modulalion of gene expression, as well as by antagonizing oxidative stress and other types of neurotoxic stress stimuli, thereby inhibiting stress-triggered cell death. We have also shown that the biochemical processing of endogenous APP is downregulated during aging of non-transformed human fibroblasts, resulting in a potently reduced secretion of APPsα. Based on these observations, we aim to 1) further investigate the potential physiological roles of APP and APLPs and their cleavage products in neuroprotection, 2) analyze the funclional consequences of APP/APLP depletion on gene expression and cellular vulnerability to neurotoxic stress, and 3) dissect the role of APP processing during neuronal and brain aging and its link to age-associated stress signaling pathways, alterations in gene expression, and oxidative changes.