The Critical Role of Nurr1 as a Mediator and Therapeutic Target in Alzheimer’s Disease-related Pathogenesis
Jeon Seong Gak1, Yoo Anji1, Chun Dong Wook1, Hong Sang Bum1, Chung Hyunju2, Kim Jin-il3,*(), Moon Minho1,*()
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
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.
● Nr4a-TKO mice cannot produce Treg cells and die early due to systemic autoimmunity
● Nurr1 induces Foxp3 in CD4+ T cells via modulating histone modifications
● Nurr1 can regulate Th17 cell-mediated autoimmune inflammation
● Nurr1 promotes cell-cycle arrest in the G1 phase as well as differentiation of MN9D cells
● Overexpression of Nurr1 inhibits proliferation via increased expression of p27Kip1 in VSM cells
● Nurr1 overexpression restricts proliferation via upregulated expression of p18 in HS cells
● Nurr1 induced after ischemic injury promotes IE cell proliferation via inhibition of p21
● Treatment with the Nurr1 agonist increases proliferation via phosphorylation of Akt and Erk1/2 in AHP cells
● Nurr1 induces neural differentiation of ECP cells through an extrinsic paracrine mechanism
● The ventral midbrain in Nurr1 knockout mice shows reduction of NPC differentiation
● Nurr1 promotes dopaminergic neuron production and suppresses inflammatory factors
● Overexpression of Nurr1 in NPCs obtained from the SVZ of rats induces dopaminergic neurons
● The Nurr1 agonist amodiaquine causes a significant increase in adult hippocampal neurogenesis
● Formation of long-term memory in the hippocampus depends on the cAMP/PKA/CREB signaling pathway, which also controls transcription of Nurr1
● 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
Vascular pathology mitigation
● Overexpression of Nurr1 inhibits vascular lesion via reducing SMCs proliferation and inflammation
● Overexpression of Nurr1 reduces oxidized-low-density lipoprotein uptake and inflammatory responses in macrophages
Role in metabolism
● Abnormal expression of Nurr1 is associated with glucose metabolism and metabolic syndrome
● NR4A receptors are induced by metabolic-related stimuli such as fatty acids, glucose and insulin
● NR4A receptors including Nurr1 are involved in increased glucose uptake in the skeletal muscle
Therapeutic potential of Nurr1 activation
● Nuclear receptors serve as a critical mediator of Aβ homeostasis
● Nurr1 expression can suppress NF-κB signaling pathway
● Nurr1 regulates AD-related pathogenesis and cognitive function in 5XFAD mice
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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