作者
Felipe Cabral‐Miranda,Giovanni Tamburini,Gabriela Martínez,Álvaro O. Ardiles,Danilo B. Medinas,Yannis Gerakis,Mei‐Li Diaz Hung,René L. Vidal,Matías Fuentealba,Tim Miedema,Claudia Durán-Aniotz,Javier Diaz,Cristobal Ibaceta‐Gonzalez,Carleen Mae P. Sabusap,Francisca Bermedo‐García,Paula Mujica,Stuart Adamson,Kaitlyn Vitangcol,Hernán Huerta Huerta,Xu Zhang,Tomohiro Nakamura,S. Pablo Sardi,Stuart A. Lipton,Brian K. Kennedy,Juan Pablo Henríquez,César Cárdenas,Lars Plate,Adrián G. Palacios,Claudio Hetz
摘要
Abstract Aging is a major risk factor to develop neurodegenerative diseases and is associated with decreased buffering capacity of the proteostasis network. We investigated the significance of the unfolded protein response (UPR), a major signaling pathway activated to cope with endoplasmic reticulum (ER) stress, in the functional deterioration of the mammalian brain during aging. We report that genetic disruption of the ER stress sensor IRE1 accelerated age‐related cognitive decline. In mouse models, overexpressing an active form of the UPR transcription factor XBP1 restored synaptic and cognitive function, in addition to reducing cell senescence. Proteomic profiling of hippocampal tissue showed that XBP1 expression significantly restore changes associated with aging, including factors involved in synaptic function and pathways linked to neurodegenerative diseases. The genes modified by XBP1 in the aged hippocampus where also altered. Collectively, our results demonstrate that strategies to manipulate the UPR in mammals may help sustain healthy brain aging.