Howard Hughes Medical Institute, Glenn Center for Aging Research, Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Cell. 2009 Dec 11;139(6):1157-69. doi: 10.1016/j.cell.2009.11.014.
The insulin/insulin growth factor (IGF) signaling (IIS) pathway is a key regulator of aging of worms, flies, mice, and likely humans. Delayed aging by IIS reduction protects the nematode C. elegans from toxicity associated with the aggregation of the Alzheimer's disease-linked human peptide, Abeta. We reduced IGF signaling in Alzheimer's model mice and discovered that these animals are protected from Alzheimer's-like disease symptoms, including reduced behavioral impairment, neuroinflammation, and neuronal loss. This protection is correlated with the hyperaggregation of Abeta leading to tightly packed, ordered plaques, suggesting that one aspect of the protection conferred by reduced IGF signaling is the sequestration of soluble Abeta oligomers into dense aggregates of lower toxicity. These findings indicate that the IGF signaling-regulated mechanism that protects from Abeta toxicity is conserved from worms to mammals and point to the modulation of this signaling pathway as a promising strategy for the development of Alzheimer's disease therapy.
胰岛素/胰岛素样生长因子（IGF）信号通路是调节蠕虫、苍蝇、老鼠以及可能人类衰老的关键。通过降低 IIS 来延缓衰老可以保护线虫秀丽隐杆线虫免受与阿尔茨海默病相关的人类肽 Abeta 聚集相关的毒性。我们在阿尔茨海默病模型小鼠中降低 IGF 信号，并发现这些动物免受类似阿尔茨海默病的症状的保护，包括行为障碍、神经炎症和神经元丧失的减少。这种保护与 Abeta 的超聚集有关，导致紧密堆积的有序斑块，表明降低 IGF 信号所赋予的保护的一个方面是将可溶性 Abeta 寡聚体隔离到毒性较低的密集聚集体中。这些发现表明，从蠕虫到哺乳动物，保护免受 Abeta 毒性的 IGF 信号调节机制是保守的，并指出调节这种信号通路是开发阿尔茨海默病治疗方法的有前途的策略。
