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.

Aging-dependent YAP1 reduction contributes to AD pathology by upregulating the Nr4a1-AKT/GSK-3β axis.

Background: Aging is the greatest risk factor for late-onset Alzheimer's disease (LOAD), which accounts for > 95% of all Alzheimer's disease (AD) cases. Yes-associated protein 1 (YAP1), an aging-dependent protein, is a key element in the classical Hippo-YAP1 pathway mediated by a kinase cascade. Research showed that YAP1 was markedly reduced in the brains of individuals with AD.