The Salk Institute for Biological Studies, Laboratory of Cellular Neurobiology, 10010 N. Torrey Pines Rd, La Jolla, CA 92037, USA.
Aging Cell. 2012 Dec;11(6):1017-26. doi: 10.1111/acel.12002. Epub 2012 Oct 1.
Mounting evidence supports a link between diabetes, cognitive dysfunction, and aging. However, the physiological mechanisms by which diabetes impacts brain function and cognition are not fully understood. To determine how diabetes contributes to cognitive dysfunction and age-associated pathology, we used streptozotocin to induce type 1 diabetes (T1D) in senescence-accelerated prone 8 (SAMP8) and senescence-resistant 1 (SAMR1) mice. Contextual fear conditioning demonstrated that T1D resulted in the development of cognitive deficits in SAMR1 mice similar to those seen in age-matched, nondiabetic SAMP8 mice. No further cognitive deficits were observed when the SAMP8 mice were made diabetic. T1D dramatically increased Aβ and glial fibrillary acidic protein immunoreactivity in the hippocampus of SAMP8 mice and to a lesser extent in age-matched SAMR1 mice. Further analysis revealed aggregated Aβ within astrocyte processes surrounding vessels. Western blot analyses from T1D SAMP8 mice showed elevated amyloid precursor protein processing and protein glycation along with increased inflammation. T1D elevated tau phosphorylation in the SAMR1 mice but did not further increase it in the SAMP8 mice where it was already significantly higher. These data suggest that aberrant glucose metabolism potentiates the aging phenotype in old mice and contributes to early stage central nervous system pathology in younger animals.
越来越多的证据表明糖尿病、认知功能障碍和衰老之间存在关联。然而，糖尿病影响大脑功能和认知的生理机制尚不完全清楚。为了确定糖尿病如何导致认知功能障碍和与年龄相关的病理变化，我们使用链脲佐菌素诱导衰老加速敏感 8 号（SAMP8）和衰老抗性 1 号（SAMR1）小鼠发生 1 型糖尿病（T1D）。情景恐惧条件反射表明，T1D 导致 SAMR1 小鼠出现认知缺陷，类似于年龄匹配的非糖尿病 SAMP8 小鼠。当 SAMP8 小鼠发生糖尿病时，没有观察到进一步的认知缺陷。T1D 显著增加了 SAMP8 小鼠海马体中的 Aβ 和神经胶质纤维酸性蛋白免疫反应性，在年龄匹配的 SAMR1 小鼠中则更为明显。进一步的分析显示，Aβ 在围绕血管的星形胶质细胞突起内聚集。来自 T1D SAMP8 小鼠的 Western blot 分析显示，淀粉样前体蛋白处理和蛋白糖化增加，同时炎症增加。T1D 增加了 SAMR1 小鼠中的 tau 磷酸化，但在 SAMP8 小鼠中没有进一步增加，因为 SAMP8 小鼠中的 tau 磷酸化已经显著升高。这些数据表明，异常的葡萄糖代谢增强了老年小鼠的衰老表型，并导致年轻动物早期中枢神经系统病理变化。
