Regulation of the cognitive aging process by the transcriptional repressor RP58

Abstract

SummaryIn humans, cognitive and motor functions develop in association with maturation, followed by a decline in advancing age. In this study, we aimed to provide a method for extending healthy lifespan by preventing age-related phenomena. Therefore, we focused on RP58, a transcriptional repressor, whose expression is reduced during aging in the human cortex. In the Rp58 hetero-knockout (KO) mice, object location memory was impaired even at 4-5 months, while it was normal in the wild-type mice at 4-5 months but was impaired at 12-18 months. These results indicate an early onset of impaired spatial memory in the mutant mice. As the underlying mechanism, the Rp58 hetero-KO mice showed early onset of DNA damage accumulation and microglial activation in the dentate gyrus due to a DNA repair defect that is generally observed with aging. As another hallmark of aging, we focused on mitochondrial function and detected mitochondrial abnormalities in the Rp58 hetero-KO mice at 4-5 months. Notably, continuous treatments with minocycline, a neuroprotective and anti-inflammatory antibiotic, prevented the facilitation of age-related phenomena in the Rp58 hetero-KO mice. These results suggest the availability of the Rp58 hetero-KO mice as a novel mouse model of human-like early aging and provide a therapeutic strategy to prevent age-related phenomena using minocycline. HighlightO_LIRp58 hetero-KO mice exhibit early aging phenotypes including impairment of spatial cognition C_LIO_LIRp58 hetero-KO mice show early accumulation of DNA damage due to a defect in the DNA repair system C_LIO_LITreatment with minocycline prevented cognitive dysfunction observed in Rp58 hetero-KO mice C_LI