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Aging and disease    2020, Vol. 11 Issue (3) : 705-724     DOI: 10.14336/AD.2019.0718
Review |
The Critical Role of Nurr1 as a Mediator and Therapeutic Target in Alzheimer’s Disease-related Pathogenesis
Seong Gak Jeon1, Anji Yoo1, Dong Wook Chun1, Sang Bum Hong1, Hyunju Chung2, Jin-il Kim3,*, Minho Moon1,*
1Department of Biochemistry, College of Medicine, Konyang University, Daejeon, 35365, Republic of Korea
2Department of Core Research Laboratory, Clinical Research Institute, Kyung Hee University Hospital at Gangdong, Seoul 05278, Republic of Korea
3Department of Nursing, College of Nursing, Jeju National University, Jeju-si 63243, Republic of Korea
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Several studies have revealed that the transcription factor nuclear receptor related 1 (Nurr1) plays several roles not only in the regulation of gene expression related to dopamine synthesis, but also in alternative splicing, and miRNA targeting. Moreover, it regulates cognitive functions and protects against inflammation-induced neuronal death. In particular, the role of Nurr1 in the pathogenesis of Parkinson’s disease (PD) has been well investigated; for example, it has been shown that it restores behavioral and histological impairments in PD models. Although many studies have evaluated the connection between Nurr1 and PD pathogenesis, the role of Nurr1 in Alzheimer’s disease (AD) remain to be studied. There have been several studies describing Nurr1 protein expression in the AD brain. However, only a few studies have examined the role of Nurr1 in the context of AD. Therefore, in this review, we highlight the overall effects of Nurr1 under the neuropathologic conditions related to AD. Furthermore, we suggest the possibility of using Nurr1 as a therapeutic target for AD or other neurodegenerative disorders.

Keywords Alzheimer’s disease      Nurr1      NR4A2      memory      neuroprotection      neuroinflammation     
Corresponding Authors: Kim Jin-il,Moon Minho   
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These authors contributed equally to this work.

Just Accepted Date: 01 August 2019   Online First Date: 02 August 2019    Issue Date: 13 May 2020
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Jeon Seong Gak
Yoo Anji
Chun Dong Wook
Hong Sang Bum
Chung Hyunju
Kim Jin-il
Moon Minho
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Jeon Seong Gak,Yoo Anji,Chun Dong Wook, et al. The Critical Role of Nurr1 as a Mediator and Therapeutic Target in Alzheimer’s Disease-related Pathogenesis[J]. Aging and disease, 2020, 11(3): 705-724.
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Nurr1 expression in AD• Nurr1 immunofluorescence intensity is reduced in the substantia nigra of AD patients[13]
• Nurr1 mRNA levels are reduced in APPswe, lnd mutant mice[62, 63]
• The number of Nurr1(+) cells is age-dependently reduced in the subiculum of 5XFAD mice[90]
• Nurr1 protein is co-localization with Aβ at the early stage in 5XFAD mice[90]
• Nurr1 protein and mRNA are downregulated in Aβ1-42 fibril-treated CGNs and the hMSC cell line[65]
Neuroprotective effects• MPTP-induced neurotoxic vulnerability of dopaminergic neurons is increased in Nurr1(+/-) mice[59]
• Nurr1 in microglia and astrocytes protects neurons by regulating the production of toxic mediators[79]
• Ligand and agonist of Nurr1 shows neuroprotective effect against oxidative insult such as MPTP and 6-OHAD[17, 19, 20]
• Increased expression of Nurr1 upregulates genes involved in ROS detoxification such as Sesn3, Alb2, and Sod1[81]
• In NSCs, the overexpression of Nurr1 protects against oxidative stress by downregulating cell death-related proteins such as caspase-3 and caspase-11[60]
• Exogenous Nurr1 induces the differentiation of dopaminergic neurons, and sustained Nurr1 expression improves survival of dopaminergic neurons[83, 149]
Anti-inflammatory effects• Nurr1 phosphorylation promotes binding to p65 and recruits the CoREST complex to promoters of inflammatory genes, resulting in inhibition of neuroinflammation[79]
• Overexpression of Nurr1 suppresses inflammation, whereas knockdown of Nurr1 enhances inflammation[16]
• NR4A receptors are involved in a negative feedback loop as modulators of the inflammation mechanism[93]
• Inflammatory stimulus (e.g., LPS) up-regulates Nurr1 mRNA expression in microglia[96]
Peripheral immune regulation• Nr4a-TKO mice cannot produce Treg cells and die early due to systemic autoimmunity[118]
• Nurr1 induces Foxp3 in CD4+ T cells via modulating histone modifications[94]
• Nurr1 can regulate Th17 cell-mediated autoimmune inflammation[112]
Cell-cycle regulation• Nurr1 promotes cell-cycle arrest in the G1 phase as well as differentiation of MN9D cells[134]
• Overexpression of Nurr1 inhibits proliferation via increased expression of p27Kip1 in VSM cells[135]
• Nurr1 overexpression restricts proliferation via upregulated expression of p18 in HS cells[136]
• Nurr1 induced after ischemic injury promotes IE cell proliferation via inhibition of p21[139]
• Treatment with the Nurr1 agonist increases proliferation via phosphorylation of Akt and Erk1/2 in AHP cells[18]
Neurogenic effects• Nurr1 induces neural differentiation of ECP cells through an extrinsic paracrine mechanism[152]
• The ventral midbrain in Nurr1 knockout mice shows reduction of NPC differentiation[150]
• Nurr1 promotes dopaminergic neuron production and suppresses inflammatory factors[155]
• Overexpression of Nurr1 in NPCs obtained from the SVZ of rats induces dopaminergic neurons[149]
• The Nurr1 agonist amodiaquine causes a significant increase in adult hippocampal neurogenesis[18]
Memory-enhancing effects• Formation of long-term memory in the hippocampus depends on the cAMP/PKA/CREB signaling pathway, which also controls transcription of Nurr1[48, 168]
• Inhibition of HDAC increases Nurr1 expression, and enhances memory, which is attenuated by protein suppression, siRNA knockdown, and Nurr1 knockout[15, 53, 54, 171]
• Dominant negative Nurr1 mice inhibition of Nurr1 function impairs hippocampal long-term potentiation[55]
Vascular pathology mitigation• Overexpression of Nurr1 inhibits vascular lesion via reducing SMCs proliferation and inflammation[135]
• Overexpression of Nurr1 reduces oxidized-low-density lipoprotein uptake and inflammatory responses in macrophages[178]
Role in metabolism• Abnormal expression of Nurr1 is associated with glucose metabolism and metabolic syndrome[183, 184]
• NR4A receptors are induced by metabolic-related stimuli such as fatty acids, glucose and insulin[185]
• NR4A receptors including Nurr1 are involved in increased glucose uptake in the skeletal muscle[186]
Therapeutic potential of Nurr1 activation• Nuclear receptors serve as a critical mediator of Aβ homeostasis[203-205]
• Nurr1 expression can suppress NF-κB signaling pathway[79]
• Nurr1 regulates AD-related pathogenesis and cognitive function in 5XFAD mice[16]
Table 1  Overview of the possible roles of Nurr1 in AD.
Figure 1.  Overview of effect of Nurr1 in Alzheimer’s disease.
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