Progressive reduction of nuclear receptor Nr4a1 mediates age-dependent cognitive decline

Jiang Chen; Zhi Zhang; Ying Liu; Lili Huang; Yi Liu; Dan Yang; Xinyu Bao; Pinyi Liu; Yuhan Ge; Qingqing Li; Xin Shu; Lushan Xu; Yun Stone Shi; Xiaolei Zhu; Yun Xu

doi:10.1002/alz.13819

Progressive reduction of nuclear receptor Nr4a1 mediates age-dependent cognitive decline

Alzheimers Dement. 2024 Apr 11. doi: 10.1002/alz.13819. Online ahead of print.

Authors

Jiang Chen^{1

2

3

4}, Zhi Zhang^{1

2

3

4}, Ying Liu^{1

2

3

4}, Lili Huang^{1

2

3

4}, Yi Liu^{1

2

3

4}, Dan Yang^{1

2

3

4}, Xinyu Bao^{1

2

3

4}, Pinyi Liu^{1

2

3

4}, Yuhan Ge^{1

2

5}, Qingqing Li^{1

2

5}, Xin Shu^{1

2

3

4}, Lushan Xu^{1

2

3

4}, Yun Stone Shi^{1

2

5}, Xiaolei Zhu^{1

2

3

4}, Yun Xu^{1

2

3

4}

Affiliations

¹ Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
² State Key Laboratory of Pharmaceutical Biotechnology and Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, China.
³ Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, China.
⁴ Nanjing Neurology Clinical Medical Center, Nanjing, China.
⁵ Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China.

PMID: 38605605
DOI: 10.1002/alz.13819

Abstract

Introduction: Cognitive decline progresses with age, and Nr4a1 has been shown to participate in memory functions. However, the relationship between age-related Nr4a1 reduction and cognitive decline is undefined.

Methods: Nr4a1 expressions were evaluated by quantitative PCR and immunochemical approaches. The cognition of mice was examined by multiple behavioral tests. Patch-clamp experiments were conducted to investigate the synaptic function.

Results: NR4A1 in peripheral blood mononuclear cells decreased with age in humans. In the mouse brain, age-dependent Nr4a1 reduction occurred in the hippocampal CA1. Deleting Nr4a1 in CA1 pyramidal neurons (PyrNs) led to the impairment of cognition and excitatory synaptic function. Mechanistically, Nr4a1 enhanced TrkB expression via binding to its promoter. Blocking TrkB compromised the cognitive amelioration with Nr4a1-overexpression in CA1 PyrNs.

Discussion: Our results elucidate the mechanism of Nr4a1-dependent TrkB regulation in cognition and synaptic function, indicating that Nr4a1 is a target for the treatment of cognitive decline.

Highlights: Nr4a1 is reduced in PBMCs and CA1 PyrNs with aging. Nr4a1 ablation in CA1 PyrNs impaired cognition and excitatory synaptic function. Nr4a1 overexpression in CA1 PyrNs ameliorated cognitive impairment of aged mice. Nr4a1 bound to TrkB promoter to enhance transcription. Blocking TrkB function compromised Nr4a1-induced cognitive improvement.

Keywords: Nr4a1; TrkB; aging; cognitive decline; synaptic plasticity.

Abstract

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