1. Unfolded protein response IRE1/XBP1 signaling is required for healthy mammalian brain aging
- Author
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Cabral‐Miranda, Felipe, Tamburini, Giovanni, Martinez, Gabriela, Ardiles, Alvaro O, Medinas, Danilo B, Gerakis, Yannis, Hung, Mei‐Li Diaz, Vidal, René, Fuentealba, Matias, Miedema, Tim, Duran‐Aniotz, Claudia, Diaz, Javier, Ibaceta‐Gonzalez, Cristobal, Sabusap, Carleen M, Bermedo‐Garcia, Francisca, Mujica, Paula, Adamson, Stuart, Vitangcol, Kaitlyn, Huerta, Hernan, Zhang, Xu, Nakamura, Tomohiro, Sardi, Sergio Pablo, Lipton, Stuart A, Kennedy, Brian K, Henriquez, Juan Pablo, Cárdenas, J Cesar, Plate, Lars, Palacios, Adrian G, and Hetz, Claudio
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Genetics ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Dementia ,Basic Behavioral and Social Science ,Aging ,Acquired Cognitive Impairment ,Alzheimer's Disease ,Neurosciences ,Behavioral and Social Science ,Neurodegenerative ,Brain Disorders ,Underpinning research ,Aetiology ,2.1 Biological and endogenous factors ,1.1 Normal biological development and functioning ,Neurological ,Animals ,Mice ,Brain ,Endoplasmic Reticulum Stress ,Protein Serine-Threonine Kinases ,Proteomics ,Signal Transduction ,Unfolded Protein Response ,X-Box Binding Protein 1 ,aging brain ,ER stress ,proteostasis ,UPR ,XBP1s ,Information and Computing Sciences ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - 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.
- Published
- 2022