The Critical Role of Nurr1 as a Mediator and Therapeutic Target in Alzheimer’s Disease-related Pathogenesis

Jeon Seong Gak, Yoo Anji, Chun Dong Wook, Hong Sang Bum, Chung Hyunju, Kim Jin-il, Moon Minho

Table 1 Overview of the possible roles of Nurr1 in AD.

	References
Nurr1 expression in AD	• Nurr1 immunofluorescence intensity is reduced in the substantia nigra of AD patients	[13]
	• Nurr1 mRNA levels are reduced in APP_{swe, 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 Aβ_1-42 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 T_reg 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]
Vascular pathology mitigation	• 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]