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

Abstract

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 inflammationinduced 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.

Pharmacological Stimulation of Nurr1 Promotes Cell Cycle Progression in Adult Hippocampal Neural Stem Cells

“…The importance of Nurr1 in PD pathology is well established [19], and reduced Nurr1 levels have been reported in AD animal models and the brains of patients with AD [112,113]. Therefore, Nurr1 has been suggested as a valid biomarker for neurodegenerative diseases and a therapeutic target [18,23]. In our studies, we reported that the pharmacological stimulation of Nurr1 could improve or restore cognitive function through adult hippocampal neurogenesis [23,38].…”

“…Therefore, Nurr1 has been suggested as a valid biomarker for neurodegenerative diseases and a therapeutic target [18,23]. In our studies, we reported that the pharmacological stimulation of Nurr1 could improve or restore cognitive function through adult hippocampal neurogenesis [23,38]. In this study, a new mechanism underlying Nurr1-mediated adult neurogenesis, i.e., through the regulation of cell cycle-related molecules, is suggested.…”

“…For Nurr1 activation, the mice were injected intraperitoneally with 20 mg/kg AQ for 14 days at 12 h intervals ( Figure S2). The AQ dose and treatment duration used in this study were obtained from reports of AQ-induced pharmacological stimulation of Nurr1 in rodents [23,38]. AQ was diluted with 0.9% saline (vehicle) and prepared just before administration (six mice per group).…”

“…In particular, Nurr1 haploinsufficiency is associated with cognitive and language impairment in humans [15,16]. Furthermore, the intracellular transcription factor Nurr1 has been suggested as a therapeutic target since it undergoes alterations and is involved in the pathology of neurodegenerative diseases including Parkinson's disease (PD) and Alzheimer's disease (AD) [17][18][19][20][21][22][23]. Despite the fact that Nurr1 is considered an orphan nuclear receptor, the endogenous ligands for Nurr1 have not yet been identified [1,2,24].…”

CK2 alpha prime and alpha-synuclein pathogenic functional interaction mediates synaptic dysregulation in Huntington’s disease

“…Nr4a2 is a nuclear receptor, also known as Nurr1, essential for the development and specification of midbrain dopamine neurons and regulated by α-syn (Decressac et al 2012). Nr4a2 expression is found to be directly induced by various stimuli such as inflammatory signals and cytokines, and although its up-regulation is often associated with protective effects, it is also an indicator of a neuroinflammatory response (Jeon et al 2020). Overall, these data suggest that CK2α’ could be modulating synaptic activity and neuroinflammation by controlling the activity of α-syn and their corresponding targets.…”