Analysis of the mechanism of pathological synaptic alterations in Alzheimer's disease

我们研究了早老素1突变引起的病理机制，早老素1是家族性阿尔茨海默病（AD）的负责蛋白。我们重点研究了胰岛素信号作为PS1的影响因子，并揭示了其对PS1定位和构象的影响。我们的研究结果表明，胰岛素抑制GSK3 β的激活，从而导致PS1磷酸化的抑制，胰岛素信号通路参与了PS1向细胞表面的易位及其切割功能。此外，我们发现胰岛素受体IR被PS1切割，然后其胞内结构域易位到细胞核，从而激活Akt的转录。综上所述，我们得出结论，胰岛素信号是由PS1调节的。接下来，我们通过给APP Tg小鼠高脂饮食，建立了一种新型糖尿病AD模型小鼠。这只老鼠表现出明显的短期记忆损伤，表明糖尿病是阿尔茨海默病的一个加重因素。

We investigated the pathological mechanisms caused by mutations of Presenilin 1, a responsible protein for familial Alzheimer's disease(AD). We focused on insulin signaling as an influential factor of PS1 and revealed its effect on the localization and conformation of PS1. Our result showed that insulin inhibited GSK3 beta activation, thus leading to inhibition of PS1 phosphorylation and that insulin signaling is involved in the translocation of PS1 to the cell surface and its cleavage functions. Furthermore, we found that insulin receptor, IR, is cleaved by PS1, then its intracellular domain translocates to the nucleus, which activates transcription of Akt. Taken together, we conclude that insulin signaling is modulated by PS1. Next, we created a novel AD model mouse with diabetic condition by giving high fat diet to APP Tg mouse. This mouse showed a marked impairment of short-term memory, suggesting that diabetes is an aggravating factor for AD.