Age-dependent elevation of Nr4a1 attenuates PI3K/AKT/GSK3β pathway and mediates tau hyperphosphorylation and cognitive impairments.

INTRODUCTION: Tau hyperphosphorylation exhibited in Alzheimer's brains is also commonly observed in aging process, however, the molecular mechanism underlying tau hyperphosphorylation in aging is largely unknown. The nuclear receptor subfamily 4 group A (Nr4a1) has been implicated in various pathophysiological processes including neurodegeneration, and was found to be increased in Alzheimer's brains. OBJECTIVES: Our study aims to investigate whether and how Nr4a1 promotes age-related tau hyperphosphorylation and cognitive decline. METHODS: Firstly, we examined Nr4a1 levels in hippocampus of Alzheimer's patients, SAMP8 and aged mice. Tau phosphorylation levels were evaluated in hippocampal Nr4a1-overexpressed wild-type mice. Bulk RNA sequencing was performed to gain insight into the molecular mechanism by which elevated Nr4a1 levels drive tau hyperphosphorylation. shNr4a1 viruses were used to knockdown Nr4a1 in senescent neurons and hippocampus of SAMP8 mice, further, tau phosphorylation levels and cognitive function were evaluated. Molecular docking studies were conducted to explore the interaction between Nr4a1 and AKT. RESULTS: Our findings revealed that Nr4a1 expression is elevated in the hippocampus of Alzheimer's patients, as well as in the hippocampi of SAMP8 mice and aged mice. Notably, in SAMP8 mice, Nr4a1 expression increased in an age-dependent manner, suggesting a positive correlation between Nr4a1 levels and aging. Further investigation showed that hippocampal overexpression of Nr4a1 in wild-type mice led to tau hyperphosphorylation and cognitive dysfunction, which could be rescued by Nr4a1 knockdown in SAMP8 mice. By means of bulk RNA sequencing, we demonstrated that Nr4a1 induced tau hyperphosphorylation through the inhibition of PI3K/AKT/GSK-3β pathway. Furthermore, blocking Nr4a1-AKT interactions using competitive peptides reversed tau hyperphosphorylation. CONCLUSION: These results supported the hypothesis that age-dependent upregulation of Nr4a1 attenuated PI3K/AKT/GSK-3β pathway, leading to tau hyperphosphorylation and cognitive decline. Nr4a1 may represent a promising therapeutic target for mitigating age-related cognitive impairments.