The effect of NR4A1 on APP metabolism and tau phosphorylation

Alzheimer's disease (AD) is characterized by senile plaques (SP) composed of β-amyloid protein (Aβ) and neurofibrillary tangles (NFTs) composed of intracellular hyperphosphorylated tau. Recently, nuclear receptor subfamily 4 group A member 1 (NR4A1) was implicated in synaptic plasticity, long-term memory formation, suggesting that it may play a role in the pathophysiology of AD. Here, we showed that the expression of NR4A1 was significantly increased in the hippocampus of APP/PS1 transgenic mice. In addition, NR4A1 overexpression in HT22 cells up-regulated APP and BACE1 levels, down-regulated ADAM10 expression, and promoted amyloidogenesis as indicated by decreased α-CTF levels and elevated β-CTF levels. Furthermore, a raised level of phospho-tau (p-tau, S396) was accompanied by p-GSK3β (S9) expression reducing, but total tau, p-tau (S262 and T231), CDK5 and ERK remained unchanged in NR4A1-overexpressing cells. Collectively, our results suggest that NR4A1 promotes the amyloidogenic processing of APP by regulating ADAM10 and BACE1 expression in HT22 cells; as well as NR4A1 accelerates tau hyperphosphorylation by GSK3β signal. Therefore, NR4A1 may play an important role in the pathogenesis of AD.