Journal
GENES & DISEASES
Volume 5, Issue 4, Pages 342-348Publisher
ELSEVIER
DOI: 10.1016/j.gendis.2018.04.008
Keywords
Alzheimer's disease (AD); ADAM10; BACE1; GSK3 beta; NR4A1; tau
Funding
- National Natural Science Foundation of China [31500821]
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Alzheimer's disease (AD) is characterized by senile plaques (SP) composed of beta-amyloid protein (A beta) 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 alpha-CTF levels and elevated beta-CTF levels. Furthermore, a raised level of phospho-tau (p-tau, S396) was accompanied by p-GSK3 beta (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 GSK3 beta signal. Therefore, NR4A1 may play an important role in the pathogenesis of AD. Copyright (C) 2018, Chongqing Medical University.
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