Please wait a minute...
 Home  About the Journal Editorial Board Aims & Scope Peer Review Policy Subscription Contact us
 
Early Edition  //  Current Issue  //  Open Special Issues  //  Archives  //  Most Read  //  Most Downloaded  //  Most Cited
Aging and disease
Review Article |
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
Download: PDF(789 KB)   HTML
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks    
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 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     E-mail: neoreva@hanmail.net;hominmoon@konyang.ac.kr
About author:

These authors contributed equally to this work.

Just Accepted Date: 01 August 2019   Online First Date: 02 August 2019   
Service
E-mail this article
E-mail Alert
RSS
Articles by authors
Jeon Seong Gak
Yoo Anji
Chun Dong Wook
Hong Sang Bum
Chung Hyunju
Kim Jin-il
Moon Minho
Cite this article:   
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, 10.14336/AD.2019.0718
URL:  
http://www.aginganddisease.org/EN/10.14336/AD.2019.0718     OR     http://www.aginganddisease.org/EN/Y/V/I/0
References
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.
[1] Germain P, Staels B, Dacquet C, Spedding M, Laudet V (2006). Overview of nomenclature of nuclear receptors. Pharmacol Rev, 58:685-704.
[2] Wang Z, Benoit G, Liu J, Prasad S, Aarnisalo P, Liu X, et al. (2003). Structure and function of Nurr1 identifies a class of ligand-independent nuclear receptors. Nature, 423:555-560.
[3] Zetterstrom RH, Williams R, Perlmann T, Olson L (1996). Cellular expression of the immediate early transcription factors Nurr1 and NGFI-B suggests a gene regulatory role in several brain regions including the nigrostriatal dopamine system. Brain Res Mol Brain Res, 41:111-120.
[4] Saucedo-Cardenas O, Conneely OM (1996). Comparative distribution of NURR1 and NUR77 nuclear receptors in the mouse central nervous system. J Mol Neurosci, 7:51-63.
[5] Luo Y (2012). The function and mechanisms of Nurr1 action in midbrain dopaminergic neurons, from development and maintenance to survival. Int Rev Neurobiol, 102:1-22.
[6] Jankovic J, Chen S, Le WD (2005). The role of Nurr1 in the development of dopaminergic neurons and Parkinson's disease. Prog Neurobiol, 77:128-138.
[7] Saucedo-Cardenas O, Quintana-Hau JD, Le WD, Smidt MP, Cox JJ, De Mayo F, et al. (1998). Nurr1 is essential for the induction of the dopaminergic phenotype and the survival of ventral mesencephalic late dopaminergic precursor neurons. Proc Natl Acad Sci U S A, 95:4013-4018.
[8] Sacchetti P, Carpentier R, Segard P, Olive-Cren C, Lefebvre P (2006). Multiple signaling pathways regulate the transcriptional activity of the orphan nuclear receptor NURR1. Nucleic Acids Res, 34:5515-5527.
[9] Pereira LA, Munita R, Gonzalez MP, Andres ME (2017). Long 3'UTR of Nurr1 mRNAs is targeted by miRNAs in mesencephalic dopamine neurons. PLoS One, 12:e0188177.
[10] Amelio AL, Caputi M, Conkright MD (2009). Bipartite functions of the CREB co-activators selectively direct alternative splicing or transcriptional activation. EMBO J, 28:2733-2747.
[11] Parra-Damas A, Rubio-Ferrarons L, Shen J, Saura CA (2017). CRTC1 mediates preferential transcription at neuronal activity-regulated CRE/TATA promoters. Sci Rep, 7:18004.
[12] Maxwell MA, Muscat GE (2006). The NR4A subgroup: Immediate early response genes with pleiotropic physiological roles. Nucl Recept Signal, 4.
[13] Chu Y, Le W, Kompoliti K, Jankovic J, Mufson EJ, Kordower JH (2006). Nurr1 in Parkinson's disease and related disorders. J Comp Neurol, 494:495-514.
[14] Werme M, Hermanson E, Carmine A, Buervenich S, Zetterstrom RH, Thoren P, et al. (2003). Decreased ethanol preference and wheel running in Nurr1-deficient mice. Eur J Neurosci, 17:2418-2424.
[15] Rojas P, Joodmardi E, Hong Y, Perlmann T, Ogren SO (2007). Adult mice with reduced Nurr1 expression: an animal model for schizophrenia. Mol Psychiatry, 12:756-766.
[16] Moon M, Jung ES, Jeon SG, Cha MY, Jang Y, Kim W, et al. (2018). Nurr1 (NR4A2) regulates Alzheimer's disease-related pathogenesis and cognitive function in the 5XFAD mouse model. Aging Cell:e12866.
[17] Hammond SL, Popichak KA, Li X, Hunt LG, Richman EH, Damale PU, et al. (2018). The Nurr1 Ligand,1,1-bis(3'-Indolyl)-1-(p-Chlorophenyl)Methane, Modulates Glial Reactivity and Is Neuroprotective in MPTP-Induced Parkinsonism. J Pharmacol Exp Ther, 365:636-651.
[18] Kim JI, Jeon SG, Kim KA, Kim YJ, Song EJ, Choi J, et al. (2016). The pharmacological stimulation of Nurr1 improves cognitive functions via enhancement of adult hippocampal neurogenesis. Stem Cell Res, 17:534-543.
[19] Kim CH, Han BS, Moon J, Kim DJ, Shin J, Rajan S, et al. (2015). Nuclear receptor Nurr1 agonists enhance its dual functions and improve behavioral deficits in an animal model of Parkinson's disease. Proc Natl Acad Sci U S A, 112:8756-8761.
[20] Smith GA, Rocha EM, Rooney T, Barneoud P, McLean JR, Beagan J, et al. (2015). A Nurr1 agonist causes neuroprotection in a Parkinson's disease lesion model primed with the toll-like receptor 3 dsRNA inflammatory stimulant poly(I:C). PLoS One, 10:e0121072.
[21] Barker WW, Luis CA, Kashuba A, Luis M, Harwood DG, Loewenstein D, et al. (2002). Relative frequencies of Alzheimer disease, Lewy body, vascular and frontotemporal dementia, and hippocampal sclerosis in the State of Florida Brain Bank. Alzheimer Dis Assoc Disord, 16:203-212.
[22] Holtzman DM, Morris JC, Goate AM (2011). Alzheimer's disease: the challenge of the second century. Sci Transl Med, 3:77sr71.
[23] Whitehouse PJ, Price DL, Struble RG, Clark AW, Coyle JT, Delon MR (1982). Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain. Science, 215:1237-1239.
[24] Lehericy S, Hirsch EC, Cervera-Pierot P, Hersh LB, Bakchine S, Piette F, et al. (1993). Heterogeneity and selectivity of the degeneration of cholinergic neurons in the basal forebrain of patients with Alzheimer's disease. J Comp Neurol, 330:15-31.
[25] Francis PT, Palmer AM, Snape M, Wilcock GK (1999). The cholinergic hypothesis of Alzheimer's disease: a review of progress. J Neurol Neurosurg Psychiatry, 66:137-147.
[26] Durazzo TC, Mattsson N, Weiner MW (2014). Smoking and increased Alzheimer's disease risk: a review of potential mechanisms. Alzheimers Dement, 10:S122-145.
[27] Kumar A, Singh A, Ekavali (2015). A review on Alzheimer's disease pathophysiology and its management: an update. Pharmacol Rep, 67:195-203.
[28] Lindsay J, Laurin D, Verreault R, Hebert R, Helliwell B, Hill GB, et al. (2002). Risk factors for Alzheimer's disease: a prospective analysis from the Canadian Study of Health and Aging. Am J Epidemiol, 156:445-453.
[29] Swerdlow RH (2007). Pathogenesis of Alzheimer’s disease. Clinical Interventions in Aging, 2:347-359.
[30] Forstl H (1998). Alzheimer's disease: the size of the problem, clinical manifestation and heterogeneity. J Neural Transm Suppl, 54:1-8.
[31] Nervi A, Reitz C, Tang M-X, Santana V, Piriz A, Reyes D, et al. (2008). Comparison of Clinical Manifestation in Familial Alzheimer's disease and Dementia with Lewy Bodies. Archives of neurology, 65:1634-1639.
[32] Nestor PJ, Scheltens P, Hodges JR (2004). Advances in the early detection of Alzheimer's disease. Nat Med, 10 Suppl:S34-41.
[33] Cummings JL (2004). Alzheimer's Disease. New England Journal of Medicine, 351:56-67.
[34] Van Cauwenberghe C, Van Broeckhoven C, Sleegers K (2016). The genetic landscape of Alzheimer disease: clinical implications and perspectives. Genet Med, 18:421-430.
[35] Bird TD (2008). Genetic aspects of Alzheimer disease. Genet Med, 10:231-239.
[36] McGleenon BM, Dynan KB, Passmore AP (1999). Acetylcholinesterase inhibitors in Alzheimer’s disease. British Journal of Clinical Pharmacology, 48:471-480.
[37] Birks J (2006). Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database Syst Rev:Cd005593.
[38] Butterfield DA, Pocernich CB (2003). The glutamatergic system and Alzheimer's disease: therapeutic implications. CNS Drugs, 17:641-652.
[39] Parsons CG, Danysz W, Dekundy A, Pulte I (2013). Memantine and Cholinesterase Inhibitors: Complementary Mechanisms in the Treatment of Alzheimer’s Disease. Neurotoxicity Research, 24:358-369.
[40] Imbimbo BP, Ottonello S, Frisardi V, Solfrizzi V, Greco A, Seripa D, et al. (2012). Solanezumab for the treatment of mild-to-moderate Alzheimer’s disease. Expert Review of Clinical Immunology, 8:135-149.
[41] Adolfsson O, Pihlgren M, Toni N, Varisco Y, Buccarello AL, Antoniello K, et al. (2012). An effector-reduced anti-beta-amyloid (Abeta) antibody with unique abeta binding properties promotes neuroprotection and glial engulfment of Abeta. J Neurosci, 32:9677-9689.
[42] Malpass K (2013). Alzheimer disease: Plaque-specific anti-A[beta] antibody shows promise in model of AD. Nat Rev Neurol, 9:61-61.
[43] Panza F, Frisardi V, Solfrizzi V, Imbimbo BP, Logroscino G, Santamato A, et al. (2012). Immunotherapy for Alzheimer's disease: from anti-beta-amyloid to tau-based immunization strategies. Immunotherapy, 4:213-238.
[44] Huang Y, Mucke L (2012). Alzheimer mechanisms and therapeutic strategies. Cell, 148:1204-1222.
[45] Selkoe DJ (1994). Alzheimer's disease: a central role for amyloid. J Neuropathol Exp Neurol, 53:438-447.
[46] LaFerla FM, Green KN, Oddo S (2007). Intracellular amyloid-beta in Alzheimer's disease. Nat Rev Neurosci, 8:499-509.
[47] Moon M, Hong HS, Nam DW, Baik SH, Song H, Kook SY, et al. (2012). Intracellular amyloid-beta accumulation in calcium-binding protein-deficient neurons leads to amyloid-beta plaque formation in animal model of Alzheimer's disease. J Alzheimers Dis, 29:615-628.
[48] Hawk JD, Abel T (2011). The role of NR4A transcription factors in memory formation. Brain Res Bull, 85:21-29.
[49] Colon-Cesario WI, Martinez-Montemayor MM, Morales S, Felix J, Cruz J, Adorno M, et al. (2006). Knockdown of Nurr1 in the rat hippocampus: implications to spatial discrimination learning and memory. Learn Mem, 13:734-744.
[50] Pena de Ortiz S, Maldonado-Vlaar CS, Carrasquillo Y (2000). Hippocampal expression of the orphan nuclear receptor gene hzf-3/nurr1 during spatial discrimination learning. Neurobiol Learn Mem, 74:161-178.
[51] Vuillermot S, Joodmardi E, Perlmann T, Ove Ogren S, Feldon J, Meyer U (2011). Schizophrenia-relevant behaviors in a genetic mouse model of constitutive Nurr1 deficiency. Genes Brain Behav, 10:589-603.
[52] McQuown SC, Barrett RM, Matheos DP, Post RJ, Rogge GA, Alenghat T, et al. (2011). HDAC3 is a critical negative regulator of long-term memory formation. J Neurosci, 31:764-774.
[53] McNulty SE, Barrett RM, Vogel-Ciernia A, Malvaez M, Hernandez N, Davatolhagh MF, et al. (2012). Differential roles for Nr4a1 and Nr4a2 in object location vs. object recognition long-term memory. Learn Mem, 19:588-592.
[54] Hawk JD, Bookout AL, Poplawski SG, Bridi M, Rao AJ, Sulewski ME, et al. (2012). NR4A nuclear receptors support memory enhancement by histone deacetylase inhibitors. J Clin Invest, 122:3593-3602.
[55] Bridi MS, Abel T (2013). The NR4A orphan nuclear receptors mediate transcription-dependent hippocampal synaptic plasticity. Neurobiol Learn Mem, 105:151-158.
[56] Barneda-Zahonero B, Servitja JM, Badiola N, Minano-Molina AJ, Fado R, Saura CA, et al. Nurr1 protein is required for N-methyl-D-aspartic acid (NMDA) receptor-mediated neuronal survival. J Biol Chem, 287:11351-11362.
[57] Volakakis N, Kadkhodaei B, Joodmardi E, Wallis K, Panman L, Silvaggi J, et al. NR4A orphan nuclear receptors as mediators of CREB-dependent neuroprotection. Proc Natl Acad Sci U S A, 107:12317-12322.
[58] Zhang T, Wang P, Ren H, Fan J, Wang G (2009). NGFI-B nuclear orphan receptor Nurr1 interacts with p53 and suppresses its transcriptional activity. Mol Cancer Res, 7:1408-1415.
[59] Le W, Conneely OM, He Y, Jankovic J, Appel SH (1999). Reduced Nurr1 expression increases the vulnerability of mesencephalic dopamine neurons to MPTP-induced injury. J Neurochem, 73:2218-2221.
[60] Sousa KM, Mira H, Hall AC, Jansson-Sjostrand L, Kusakabe M, Arenas E (2007). Microarray analyses support a role for Nurr1 in resistance to oxidative stress and neuronal differentiation in neural stem cells. Stem Cells, 25:511-519.
[61] Kim KS (2017). Toward neuroprotective treatments of Parkinson's disease. Proc Natl Acad Sci U S A, 114:3795-3797.
[62] Espana J, Valero J, Minano-Molina AJ, Masgrau R, Martin E, Guardia-Laguarta C, et al. (2010). beta-Amyloid disrupts activity-dependent gene transcription required for memory through the CREB coactivator CRTC1. J Neurosci, 30:9402-9410.
[63] Parra-Damas A, Valero J, Chen M, Espana J, Martin E, Ferrer I, et al. (2014). Crtc1 activates a transcriptional program deregulated at early Alzheimer's disease-related stages. J Neurosci, 34:5776-5787.
[64] Moon M, Jeong I, Kim CH, Kim J, Lee PK, Mook-Jung I, et al. (2015). Correlation between orphan nuclear receptor Nurr1 expression and amyloid deposition in 5XFAD mice, an animal model of Alzheimer's disease. J Neurochem, 132:254-262.
[65] Terzioglu-Usak S, Negis Y, Karabulut DS, Zaim M, Isik S (2017). Cellular Model of Alzheimer's Disease: Abeta1-42 Peptide Induces Amyloid Deposition and a Decrease in Topo Isomerase IIbeta and Nurr1 Expression. Curr Alzheimer Res, 14:636-644.
[66] Annese A, Manzari C, Lionetti C, Picardi E, Horner DS, Chiara M, et al. (2018). Whole transcriptome profiling of Late-Onset Alzheimer's Disease patients provides insights into the molecular changes involved in the disease. Sci Rep, 8:4282.
[67] Cotman CW, Su JH (1996). Mechanisms of neuronal death in Alzheimer's disease. Brain Pathol, 6:493-506.
[68] Levy OA, Malagelada C, Greene LA (2009). Cell death pathways in Parkinson's disease: proximal triggers, distal effectors, and final steps. Apoptosis, 14:478-500.
[69] Benn SC, Woolf CJ (2005). How do adult neurons survive? Discov Med, 5:309-318.
[70] Koo KA, Kim SH, Oh TH, Kim YC (2006). Acteoside and its aglycones protect primary cultures of rat cortical cells from glutamate-induced excitotoxicity. Life Sci, 79:709-716.
[71] Wang X (2009). The antiapoptotic activity of melatonin in neurodegenerative diseases. CNS Neurosci Ther, 15:345-357.
[72] Pan T, Zhu W, Zhao H, Deng H, Xie W, Jankovic J, et al. (2008). Nurr1 deficiency predisposes to lactacystin-induced dopaminergic neuron injury in vitro and in vivo. Brain Res, 1222:222-229.
[73] Bensinger SJ, Tontonoz P (2009). A Nurr1 pathway for neuroprotection. Cell, 137:26-28.
[74] Lin X, Parisiadou L, Sgobio C, Liu G, Yu J, Sun L, et al. (2012). Conditional expression of Parkinson's disease-related mutant alpha-synuclein in the midbrain dopaminergic neurons causes progressive neurodegeneration and degradation of transcription factor nuclear receptor related 1. J Neurosci, 32:9248-9264.
[75] Lallier SW, Graf AE, Waidyarante GR, Rogers LK (2016). Nurr1 expression is modified by inflammation in microglia. Neuroreport, 27:1120-1127.
[76] Lee MK, Nikodem VM (2004). Differential role of ERK in cAMP-induced Nurr1 expression in N2A and C6 cells. Neuroreport, 15:99-102.
[77] O'Kane M, Markham T, McEvoy AN, Fearon U, Veale DJ, FitzGerald O, et al. (2008). Increased expression of the orphan nuclear receptor NURR1 in psoriasis and modulation following TNF-alpha inhibition. J Invest Dermatol, 128:300-310.
[78] Zetterström RH, Solomin L, Jansson L, Hoffer BJ, Olson L, Perlmann T (1997). Dopamine Neuron Agenesis in Nurr1-Deficient Mice. Science, 276:248-250.
[79] Saijo K, Winner B, Carson CT, Collier JG, Boyer L, Rosenfeld MG, et al. (2009). A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death. Cell, 137:47-59.
[80] Garcia-Yague AJ, Rada P, Rojo AI, Lastres-Becker I, Cuadrado A (2013). Nuclear import and export signals control the subcellular localization of Nurr1 protein in response to oxidative stress. J Biol Chem, 288:5506-5517.
[81] Volakakis N, Kadkhodaei B, Joodmardi E, Wallis K, Panman L, Silvaggi J, et al. (2010). NR4A orphan nuclear receptors as mediators of CREB-dependent neuroprotection. Proc Natl Acad Sci U S A, 107:12317-12322.
[82] Lee MA, Lee HS, Lee HS, Cho KG, Jin BK, Sohn S, et al. (2002). Overexpression of midbrain-specific transcription factor Nurr1 modifies susceptibility of mouse neural stem cells to neurotoxins. Neurosci Lett, 333:74-78.
[83] Jo AY, Kim MY, Lee HS, Rhee YH, Lee JE, Baek KH, et al. (2009). Generation of dopamine neurons with improved cell survival and phenotype maintenance using a degradation-resistant nurr1 mutant. Stem Cells, 27:2238-2246.
[84] Bruning JM, Wang Y, Oltrabella F, Tian B, Kholodar SA, Liu H, et al. (2019). Covalent Modification and Regulation of the Nuclear Receptor Nurr1 by a Dopamine Metabolite. Cell Chem Biol, 26:674-685.e676.
[85] Li Y, Sun H, Chen Z, Xu H, Bu G, Zheng H (2016). Implications of GABAergic Neurotransmission in Alzheimer's Disease. Front Aging Neurosci, 8:31.
[86] Limon A, Reyes-Ruiz JM, Miledi R (2012). Loss of functional GABA(A) receptors in the Alzheimer diseased brain. Proc Natl Acad Sci U S A, 109:10071-10076.
[87] Kabba JA, Xu Y, Christian H, Ruan W, Chenai K, Xiang Y, et al. (2018). Microglia: Housekeeper of the Central Nervous System. Cell Mol Neurobiol, 38:53-71.
[88] Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, et al. (2015). Neuroinflammation in Alzheimer's disease. Lancet Neurol, 14:388-405.
[89] Block ML, Zecca L, Hong JS (2007). Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci, 8:57-69.
[90] Moon M, Choi JG, Nam DW, Hong HS, Choi YJ, Oh MS, et al. (2011). Ghrelin ameliorates cognitive dysfunction and neurodegeneration in intrahippocampal amyloid-beta1-42 oligomer-injected mice. J Alzheimers Dis, 23:147-159.
[91] Moon M, Choi JG, Kim SY, Oh MS (2014). Bombycis excrementum reduces amyloid-beta oligomer-induced memory impairments, neurodegeneration, and neuroinflammation in mice. J Alzheimers Dis, 41:599-613.
[92] Moon M, Kim HG, Choi JG, Oh H, Lee PK, Ha SK, et al. (2014). 6-Shogaol, an active constituent of ginger, attenuates neuroinflammation and cognitive deficits in animal models of dementia. Biochem Biophys Res Commun, 449:8-13.
[93] Rodriguez-Calvo R, Tajes M, Vazquez-Carrera M (2017). The NR4A subfamily of nuclear receptors: potential new therapeutic targets for the treatment of inflammatory diseases. Expert Opin Ther Targets, 21:291-304.
[94] Sekiya T, Kashiwagi I, Inoue N, Morita R, Hori S, Waldmann H, et al. (2011). The nuclear orphan receptor Nr4a2 induces Foxp3 and regulates differentiation of CD4+ T cells. Nat Commun, 2:269.
[95] McMorrow JP, Murphy EP (2011). Inflammation: a role for NR4A orphan nuclear receptors? Biochem Soc Trans, 39:688-693.
[96] Fan X, Luo G, Ming M, Pu P, Li L, Yang D, et al. (2009). Nurr1 expression and its modulation in microglia. Neuroimmunomodulation, 16:162-170.
[97] Alvarez-Castelao B, Losada F, Ahicart P, Castano JG (2013). The N-terminal region of Nurr1 (a.a 1-31) is essential for its efficient degradation by the ubiquitin proteasome pathway. PLoS One, 8:e55999.
[98] Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, et al. (2000). Inflammation and Alzheimer's disease. Neurobiol Aging, 21:383-421.
[99] Kalaria RN (1999). The blood-brain barrier and cerebrovascular pathology in Alzheimer's disease. Ann N Y Acad Sci, 893:113-125.
[100] Togo T, Akiyama H, Iseki E, Kondo H, Ikeda K, Kato M, et al. (2002). Occurrence of T cells in the brain of Alzheimer's disease and other neurological diseases. J Neuroimmunol, 124:83-92.
[101] Saresella M, Calabrese E, Marventano I, Piancone F, Gatti A, Alberoni M, et al. (2011). Increased activity of Th-17 and Th-9 lymphocytes and a skewing of the post-thymic differentiation pathway are seen in Alzheimer's disease. Brain Behav Immun, 25:539-547.
[102] Yin Y, Wen S, Li G, Wang D (2009). Hypoxia enhances stimulating effect of amyloid beta peptide (25-35) for interleukin 17 and T helper lymphocyte subtype 17 upregulation in cultured peripheral blood mononuclear cells. Microbiol Immunol, 53:281-286.
[103] Browne TC, McQuillan K, McManus RM, O'Reilly JA, Mills KH, Lynch MA (2013). IFN-gamma Production by amyloid beta-specific Th1 cells promotes microglial activation and increases plaque burden in a mouse model of Alzheimer's disease. J Immunol, 190:2241-2251.
[104] Zhang J, Ke KF, Liu Z, Qiu YH, Peng YP (2013). Th17 cell-mediated neuroinflammation is involved in neurodegeneration of abeta1-42-induced Alzheimer's disease model rats. PLoS One, 8:e75786.
[105] Fisher Y, Nemirovsky A, Baron R, Monsonego A (2010). T cells specifically targeted to amyloid plaques enhance plaque clearance in a mouse model of Alzheimer's disease. PLoS One, 5:e10830.
[106] Lambracht-Washington D, Qu BX, Fu M, Anderson LD, Jr., Stuve O, Eagar TN, et al. (2011). DNA immunization against amyloid beta 42 has high potential as safe therapy for Alzheimer's disease as it diminishes antigen-specific Th1 and Th17 cell proliferation. Cell Mol Neurobiol, 31:867-874.
[107] Navone ND, Perga S, Martire S, Berchialla P, Malucchi S, Bertolotto A (2014). Monocytes and CD4+ T cells contribution to the under-expression of NR4A2 and TNFAIP3 genes in patients with multiple sclerosis. J Neuroimmunol, 272:99-102.
[108] Gilli F, Lindberg RL, Valentino P, Marnetto F, Malucchi S, Sala A, et al. (2010). Learning from nature: pregnancy changes the expression of inflammation-related genes in patients with multiple sclerosis. PLoS One, 5:e8962.
[109] Achiron A, Grotto I, Balicer R, Magalashvili D, Feldman A, Gurevich M (2010). Microarray analysis identifies altered regulation of nuclear receptor family members in the pre-disease state of multiple sclerosis. Neurobiol Dis, 38:201-209.
[110] Satoh J, Nakanishi M, Koike F, Onoue H, Aranami T, Yamamoto T, et al. (2006). T cell gene expression profiling identifies distinct subgroups of Japanese multiple sclerosis patients. J Neuroimmunol, 174:108-118.
[111] Kawakami N, Nagerl UV, Odoardi F, Bonhoeffer T, Wekerle H, Flugel A (2005). Live imaging of effector cell trafficking and autoantigen recognition within the unfolding autoimmune encephalomyelitis lesion. J Exp Med, 201:1805-1814.
[112] Raveney BJ, Oki S, Yamamura T (2013). Nuclear receptor NR4A2 orchestrates Th17 cell-mediated autoimmune inflammation via IL-21 signalling. PLoS One, 8:e56595.
[113] Shinji O (2014). Towards understanding the role of orphan nuclear receptor NR4A2 in Th17 cell-mediated central nervous system autoimmunity: An experimental approach using an animal model of multiple sclerosis. Clinical and Experimental Neuroimmunology, 5:137-148.
[114] Montarolo F, Perga S, Martire S, Bertolotto A (2015). Nurr1 reduction influences the onset of chronic EAE in mice. Inflamm Res, 64:841-844.
[115] Ralph JA, McEvoy AN, Kane D, Bresnihan B, FitzGerald O, Murphy EP (2005). Modulation of orphan nuclear receptor NURR1 expression by methotrexate in human inflammatory joint disease involves adenosine A2A receptor-mediated responses. J Immunol, 175:555-565.
[116] Cheng LE, Chan FK, Cado D, Winoto A (1997). Functional redundancy of the Nur77 and Nor-1 orphan steroid receptors in T-cell apoptosis. EMBO J, 16:1865-1875.
[117] Moran AE, Holzapfel KL, Xing Y, Cunningham NR, Maltzman JS, Punt J, et al. (2011). T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse. J Exp Med, 208:1279-1289.
[118] Sekiya T, Kashiwagi I, Yoshida R, Fukaya T, Morita R, Kimura A, et al. (2013). Nr4a receptors are essential for thymic regulatory T cell development and immune homeostasis. Nat Immunol, 14:230-237.
[119] Marsh SE, Abud EM, Lakatos A, Karimzadeh A, Yeung ST, Davtyan H, et al. (2016). The adaptive immune system restrains Alzheimer's disease pathogenesis by modulating microglial function. Proc Natl Acad Sci U S A, 113:E1316-1325.
[120] Le Page A, Dupuis G, Frost EH, Larbi A, Pawelec G, Witkowski JM, et al. (2018). Role of the peripheral innate immune system in the development of Alzheimer's disease. Exp Gerontol, 107:59-66.
[121] Vincent I, Jicha G, Rosado M, Dickson DW (1997). Aberrant expression of mitotic cdc2/cyclin B1 kinase in degenerating neurons of Alzheimer's disease brain. J Neurosci, 17:3588-3598.
[122] Frade JM, Ovejero-Benito MC (2015). Neuronal cell cycle: the neuron itself and its circumstances. Cell Cycle, 14:712-720.
[123] Yang Y, Geldmacher DS, Herrup K (2001). DNA replication precedes neuronal cell death in Alzheimer's disease. J Neurosci, 21:2661-2668.
[124] Yang Y, Mufson EJ, Herrup K (2003). Neuronal cell death is preceded by cell cycle events at all stages of Alzheimer's disease. J Neurosci, 23:2557-2563.
[125] Casadesus G, Gutierrez-Cuesta J, Lee HG, Jimenez A, Tajes M, Ortuno-Sahagun D, et al. (2012). Neuronal cell cycle re-entry markers are altered in the senescence accelerated mouse P8 (SAMP8). J Alzheimers Dis, 30:573-583.
[126] Patrick GN, Zukerberg L, Nikolic M, de la Monte S, Dikkes P, Tsai LH (1999). Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature, 402:615-622.
[127] Seward ME, Swanson E, Norambuena A, Reimann A, Cochran JN, Li R, et al. (2013). Amyloid-beta signals through tau to drive ectopic neuronal cell cycle re-entry in Alzheimer's disease. J Cell Sci, 126:1278-1286.
[128] Iijima K, Ando K, Takeda S, Satoh Y, Seki T, Itohara S, et al. (2000). Neuron-specific phosphorylation of Alzheimer's beta-amyloid precursor protein by cyclin-dependent kinase 5. J Neurochem, 75:1085-1091.
[129] Liu F, Su Y, Li B, Zhou Y, Ryder J, Gonzalez-DeWhitt P, et al. (2003). Regulation of amyloid precursor protein (APP) phosphorylation and processing by p35/Cdk5 and p25/Cdk5. FEBS Lett, 547:193-196.
[130] Suzuki T, Oishi M, Marshak DR, Czernik AJ, Nairn AC, Greengard P (1994). Cell cycle-dependent regulation of the phosphorylation and metabolism of the Alzheimer amyloid precursor protein. EMBO J, 13:1114-1122.
[131] Lee MS, Kao SC, Lemere CA, Xia W, Tseng HC, Zhou Y, et al. (2003). APP processing is regulated by cytoplasmic phosphorylation. J Cell Biol, 163:83-95.
[132] Bai B (2018). U1 snRNP Alteration and Neuronal Cell Cycle Reentry in Alzheimer Disease. Front Aging Neurosci, 10:75.
[133] Kroemer G, Galluzzi L, Vandenabeele P, Abrams J, Alnemri ES, Baehrecke EH, et al. (2009). Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ, 16:3-11.
[134] Castro DS, Hermanson E, Joseph B, Wallen A, Aarnisalo P, Heller A, et al. (2001). Induction of cell cycle arrest and morphological differentiation by Nurr1 and retinoids in dopamine MN9D cells. J Biol Chem, 276:43277-43284.
[135] Bonta PI, Pols TW, van Tiel CM, Vos M, Arkenbout EK, Rohlena J, et al. (2010). Nuclear receptor Nurr1 is expressed in and is associated with human restenosis and inhibits vascular lesion formation in mice involving inhibition of smooth muscle cell proliferation and inflammation. Circulation, 121:2023-2032.
[136] Sirin O, Lukov GL, Mao R, Conneely OM, Goodell MA (2010). The orphan nuclear receptor Nurr1 restricts the proliferation of haematopoietic stem cells. Nat Cell Biol, 12:1213-1219.
[137] Maijenburg MW, Gilissen C, Melief SM, Kleijer M, Weijer K, Ten Brinke A, et al. (2012). Nuclear receptors Nur77 and Nurr1 modulate mesenchymal stromal cell migration. Stem Cells Dev, 21:228-238.
[138] Vergano-Vera E, Diaz-Guerra E, Rodriguez-Traver E, Mendez-Gomez HR, Solis O, Pignatelli J, et al. (2015). Nurr1 blocks the mitogenic effect of FGF-2 and EGF, inducing olfactory bulb neural stem cells to adopt dopaminergic and dopaminergic-GABAergic neuronal phenotypes. Dev Neurobiol, 75:823-841.
[139] Zu G, Yao J, Ji A, Ning S, Luo F, Li Z, et al. (2017). Nurr1 promotes intestinal regeneration after ischemia/reperfusion injury by inhibiting the expression of p21 (Waf1/Cip1). J Mol Med (Berl), 95:83-95.
[140] Goncalves JT, Schafer ST, Gage FH (2016). Adult Neurogenesis in the Hippocampus: From Stem Cells to Behavior. Cell, 167:897-914.
[141] Gage FH (2000). Mammalian neural stem cells. Science, 287:1433-1438.
[142] Piatti VC, Ewell LA, Leutgeb JK (2013). Neurogenesis in the dentate gyrus: carrying the message or dictating the tone. Front Neurosci, 7:50.
[143] Deng W, Aimone JB, Gage FH (2010). New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nat Rev Neurosci, 11:339-350.
[144] Mu Y, Gage FH (2011). Adult hippocampal neurogenesis and its role in Alzheimer's disease. Mol Neurodegener, 6:85.
[145] Lazarov O, Marr RA (2010). Neurogenesis and Alzheimer's disease: At the crossroads. Experimental Neurology, 223:267-281.
[146] Church RM, Miller MC, Freestone D, Chiu C, Osgood DP, Machan JT, et al. (2014). Amyloid-beta accumulation, neurogenesis, behavior, and the age of rats. Behav Neurosci, 128:523-536.
[147] Wang B, Wang Z, Sun L, Yang L, Li H, Cole AL, et al. (2014). The amyloid precursor protein controls adult hippocampal neurogenesis through GABAergic interneurons. J Neurosci, 34:13314-13325.
[148] Zhang W, Thevapriya S, Kim PJ, Yu WP, Je HS, Tan EK, et al. (2014). Amyloid precursor protein regulates neurogenesis by antagonizing miR-574-5p in the developing cerebral cortex. Nat Commun, 5:3330.
[149] Shim JW, Park CH, Bae YC, Bae JY, Chung S, Chang MY, et al. (2007). Generation of functional dopamine neurons from neural precursor cells isolated from the subventricular zone and white matter of the adult rat brain using Nurr1 overexpression. Stem Cells, 25:1252-1262.
[150] Le W-d, Conneely OM, Zou L, He Y, Saucedo-Cardenas O, Jankovic J, et al. (1999). Selective Agenesis of Mesencephalic Dopaminergic Neurons in Nurr1-Deficient Mice. Experimental Neurology, 159:451-458.
[151] Kim J-H, Auerbach JM, Rodríguez-Gómez JA, Velasco I, Gavin D, Lumelsky N, et al. (2002). Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson's disease. Nature, 418:50.
[152] Bae EJ, Lee HS, Park CH, Lee SH (2009). Orphan nuclear receptor Nurr1 induces neuron differentiation from embryonic cortical precursor cells via an extrinsic paracrine mechanism. FEBS Lett, 583:1505-1510.
[153] Hara K, Matsukawa N, Yasuhara T, Xu L, Yu G, Maki M, et al. (2007). Transplantation of post-mitotic human neuroteratocarcinoma-overexpressing Nurr1 cells provides therapeutic benefits in experimental stroke: in vitro evidence of expedited neuronal differentiation and GDNF secretion. J Neurosci Res, 85:1240-1251.
[154] Park CH, Kang JS, Yoon EH, Shim JW, Suh-Kim H, Lee SH (2008). Proneural bHLH neurogenin 2 differentially regulates Nurr1-induced dopamine neuron differentiation in rat and mouse neural precursor cells in vitro. FEBS Lett, 582:537-542.
[155] Chen X, Qian Y, Wang X, Tang Z, Xu J, Lin H, et al. (2018). Nurr1 promotes neurogenesis of dopaminergic neuron and represses inflammatory factors in the transwell coculture system of neural stem cells and microglia. CNS Neurosci Ther.
[156] Ahn JH, Lee JS, Cho JH, Park JH, Lee TK, Song M, et al. (2018). Age-dependent decrease of Nurr1 protein expression in the gerbil hippocampus. Biomed Rep, 8:517-522.
[157] Morley JE, Farr SA (2014). The role of amyloid-beta in the regulation of memory. Biochem Pharmacol, 88:479-485.
[158] Chen G, Chen KS, Knox J, Inglis J, Bernard A, Martin SJ, et al. (2000). A learning deficit related to age and beta-amyloid plaques in a mouse model of Alzheimer's disease. Nature, 408:975-979.
[159] Lopez-Toledano MA, Ali Faghihi M, Patel NS, Wahlestedt C (2010). Adult neurogenesis: a potential tool for early diagnosis in Alzheimer's disease? J Alzheimers Dis, 20:395-408.
[160] Lin CH, Huang YJ, Lin CJ, Lane HY, Tsai GE (2014). NMDA neurotransmission dysfunction in mild cognitive impairment and Alzheimer's disease. Curr Pharm Des, 20:5169-5179.
[161] Zhang Y, Li P, Feng J, Wu M (2016). Dysfunction of NMDA receptors in Alzheimer's disease. Neurol Sci, 37:1039-1047.
[162] Josselyn SA, Nguyen PV (2005). CREB, synapses and memory disorders: Past progress and future challenges. Current Drug Targets: CNS and Neurological Disorders, 4:481-497.
[163] Lemberger T, Parkitna JR, Chai M, Schütz G, Engblom D (2008). CREB has a context-dependent role in activity-regulated transcription and maintains neuronal cholesterol homeostasis. FASEB Journal, 22:2872-2879.
[164] Abel T, Nguyen PV, Barad M, Deuel TAS, Kandel ER, Bourtchouladze R (1997). Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus-based long-term memory. Cell, 88:615-626.
[165] Huang Yan Y, Kandel ER (1994). Recruitment of long-lasting and protein kinase A-dependent long-term potentiation in the CA1 region of hippocampus requires repeated tetanization. Learning Memory, 1:74-82.
[166] Igaz LM, Vianna MRM, Medina JH, Izquierdo I (2002). Two time periods of hippocampal mRNA synthesis are required for memory consolidation of fear-motivated learning. Journal of Neuroscience, 22:6781-6789.
[167] Nguyen PV, Abel T, Kandel ER (1994). Requirement of a critical period of transcription for induction of a late phase of LTP. Science, 265:1104-1107.
[168] Pittenger C, Huang YY, Paletzki RF, Bourtchouladze R, Scanlin H, Vronskaya S, et al. (2002). Reversible inhibition of CREB/ATF transcription factors in region CA1 of the dorsal hippocampus disrupts hippocampus-dependent spatial memory. Neuron, 34:447-462.
[169] Ryan MM, Mason-Parker SE, Tate WP, Abraham WC, Williams JM (2011). Rapidly induced gene networks following induction of long-term potentiation at perforant path synapses in vivo. Hippocampus, 21:541-553.
[170] Pegoraro S, Broccard FD, Ruaro ME, Bianchini D, Avossa D, Pastore G, et al. (2010). Sequential steps underlying neuronal plasticity induced by a transient exposure to gabazine. Journal of Cellular Physiology, 222:713-728.
[171] Vecsey CG, Hawk JD, Lattal KM, Stein JM, Fabian SA, Attner MA, et al. (2007). Histone deacetylase inhibitors enhance memory and synaptic plasticity via CREB: CBP-dependent transcriptional activation. Journal of Neuroscience, 27:6128-6140.
[172] Clarke SE, Jukes MC, Njagi JK, Khasakhala L, Cundill B, Otido J, et al. (2008). Effect of intermittent preventive treatment of malaria on health and education in schoolchildren: a cluster-randomised, double-blind, placebo-controlled trial. Lancet, 372:127-138.
[173] Biffi A, Greenberg SM (2011). Cerebral amyloid angiopathy: a systematic review. J Clin Neurol, 7:1-9.
[174] McCarron MO, Nicoll JA (2004). Cerebral amyloid angiopathy and thrombolysis-related intracerebral haemorrhage. Lancet Neurol, 3:484-492.
[175] Attems J, Jellinger K, Thal DR, Van Nostrand W (2011). Review: sporadic cerebral amyloid angiopathy. Neuropathol Appl Neurobiol, 37:75-93.
[176] Selkoe DJ (2001). Alzheimer's disease: genes, proteins, and therapy. Physiol Rev, 81:741-766.
[177] Pei L, Castrillo A, Chen M, Hoffmann A, Tontonoz P (2005). Induction of NR4A orphan nuclear receptor expression in macrophages in response to inflammatory stimuli. J Biol Chem, 280:29256-29262.
[178] Bonta PI, van Tiel CM, Vos M, Pols TW, van Thienen JV, Ferreira V, et al. (2006). Nuclear receptors Nur77, Nurr1, and NOR-1 expressed in atherosclerotic lesion macrophages reduce lipid loading and inflammatory responses. Arterioscler Thromb Vasc Biol, 26:2288-2294.
[179] Kim B, Backus C, Oh S, Hayes JM, Feldman EL (2009). Increased tau phosphorylation and cleavage in mouse models of type 1 and type 2 diabetes. Endocrinology, 150:5294-5301.
[180] Ott A, Stolk RP, van Harskamp F, Pols HA, Hofman A, Breteler MM (1999). Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology, 53:1937-1942.
[181] Whitmer RA, Gunderson EP, Quesenberry CP, Jr., Zhou J, Yaffe K (2007). Body mass index in midlife and risk of Alzheimer disease and vascular dementia. Curr Alzheimer Res, 4:103-109.
[182] Cai H, Cong WN, Ji S, Rothman S, Maudsley S, Martin B (2012). Metabolic dysfunction in Alzheimer's disease and related neurodegenerative disorders. Curr Alzheimer Res, 9:5-17.
[183] Zhao Y, Bruemmer D (2010). NR4A orphan nuclear receptors: transcriptional regulators of gene expression in metabolism and vascular biology. Arterioscler Thromb Vasc Biol, 30:1535-1541.
[184] Xu Y, Huang Q, Zhang W, Wang Y, Zeng Q, He C, et al. (2015). Decreased expression levels of Nurr1 are associated with chronic inflammation in patients with type 2 diabetes. Mol Med Rep, 12:5487-5493.
[185] Pearen MA, Muscat GE (2010). Minireview: Nuclear hormone receptor 4A signaling: implications for metabolic disease. Mol Endocrinol, 24:1891-1903.
[186] Close AF, Rouillard C, Buteau J (2013). NR4A orphan nuclear receptors in glucose homeostasis: a minireview. Diabetes Metab, 39:478-484.
[187] Sutherland RJ (1982). The dorsal diencephalic conduction system: a review of the anatomy and functions of the habenular complex. Neurosci Biobehav Rev, 6:1-13.
[188] Groenewegen HJ, Ahlenius S, Haber SN, Kowall NW, Nauta WJ (1986). Cytoarchitecture, fiber connections, and some histochemical aspects of the interpeduncular nucleus in the rat. J Comp Neurol, 249:65-102.
[189] Herkenham M, Nauta WJ (1979). Efferent connections of the habenular nuclei in the rat. J Comp Neurol, 187:19-47.
[190] Jhou TC, Geisler S, Marinelli M, Degarmo BA, Zahm DS (2009). The mesopontine rostromedial tegmental nucleus: A structure targeted by the lateral habenula that projects to the ventral tegmental area of Tsai and substantia nigra compacta. J Comp Neurol, 513:566-596.
[191] Lecourtier L, Kelly PH (2007). A conductor hidden in the orchestra? Role of the habenular complex in monoamine transmission and cognition. Neurosci Biobehav Rev, 31:658-672.
[192] Hikosaka O (2010). The habenula: from stress evasion to value-based decision-making. Nat Rev Neurosci, 11:503-513.
[193] Contestabile A, Villani L, Fasolo A, Franzoni MF, Gribaudo L, Oktedalen O, et al. (1987). Topography of cholinergic and substance P pathways in the habenulo-interpeduncular system of the rat. An immunocytochemical and microchemical approach. Neuroscience, 21:253-270.
[194] Lein ES, Hawrylycz MJ, Ao N, Ayres M, Bensinger A, Bernard A, et al. (2007). Genome-wide atlas of gene expression in the adult mouse brain. Nature, 445:168-176.
[195] Quina LA, Wang S, Ng L, Turner EE (2009). Brn3a and Nurr1 mediate a gene regulatory pathway for habenula development. J Neurosci, 29:14309-14322.
[196] Caldecott-Hazard S, Mazziotta J, Phelps M (1988). Cerebral correlates of depressed behavior in rats, visualized using 14C-2-deoxyglucose autoradiography. J Neurosci, 8:1951-1961.
[197] Shumake J, Edwards E, Gonzalez-Lima F (2003). Opposite metabolic changes in the habenula and ventral tegmental area of a genetic model of helpless behavior. Brain Res, 963:274-281.
[198] Morris JS, Smith KA, Cowen PJ, Friston KJ, Dolan RJ (1999). Covariation of activity in habenula and dorsal raphe nuclei following tryptophan depletion. Neuroimage, 10:163-172.
[199] Sartorius A, Kiening KL, Kirsch P, von Gall CC, Haberkorn U, Unterberg AW, et al. (2010). Remission of major depression under deep brain stimulation of the lateral habenula in a therapy-refractory patient. Biol Psychiatry, 67:e9-e11.
[200] Chen CH, Zhou W, Liu S, Deng Y, Cai F, Tone M, et al. (2012). Increased NF-kappaB signalling up-regulates BACE1 expression and its therapeutic potential in Alzheimer's disease. Int J Neuropsychopharmacol, 15:77-90.
[201] Maira M, Martens C, Philips A, Drouin J (1999). Heterodimerization between members of the Nur subfamily of orphan nuclear receptors as a novel mechanism for gene activation. Mol Cell Biol, 19:7549-7557.
[202] Cramer PE, Cirrito JR, Wesson DW, Lee CY, Karlo JC, Zinn AE, et al. (2012). ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models. Science, 335:1503-1506.
[203] Heneka MT, Reyes-Irisarri E, Hull M, Kummer MP (2011). Impact and Therapeutic Potential of PPARs in Alzheimer's Disease. Curr Neuropharmacol, 9:643-650.
[204] Mandrekar-Colucci S, Karlo JC, Landreth GE (2012). Mechanisms underlying the rapid peroxisome proliferator-activated receptor-gamma-mediated amyloid clearance and reversal of cognitive deficits in a murine model of Alzheimer's disease. J Neurosci, 32:10117-10128.
[205] Mandrekar-Colucci S, Landreth GE (2011). Nuclear receptors as therapeutic targets for Alzheimer's disease. Expert Opin Ther Targets, 15:1085-1097.
[206] Dubois C, Hengerer B, Mattes H (2006). Identification of a potent agonist of the orphan nuclear receptor Nurr1. ChemMedChem, 1:955-958.
[207] Hintermann S, Chiesi M, von Krosigk U, Mathe D, Felber R, Hengerer B (2007). Identification of a series of highly potent activators of the Nurr1 signaling pathway. Bioorg Med Chem Lett, 17:193-196.
[208] Poppe L, Harvey TS, Mohr C, Zondlo J, Tegley CM, Nuanmanee O, et al. (2007). Discovery of ligands for Nurr1 by combined use of NMR screening with different isotopic and spin-labeling strategies. J Biomol Screen, 12:301-311.
[209] Kim CH, Leblanc P, Kim KS (2016). 4-amino-7-chloroquinoline derivatives for treating Parkinson's disease: implications for drug discovery. Expert Opin Drug Discov, 11:337-341.
[210] Montarolo F, Raffaele C, Perga S, Martire S, Finardi A, Furlan R, et al. (2014). Effects of isoxazolo-pyridinone 7e, a potent activator of the Nurr1 signaling pathway, on experimental autoimmune encephalomyelitis in mice. PLoS One, 9:e108791.
[211] Lesuisse D, Malanda A, Peyronel JF, Evanno Y, Lardenois P, De-Peretti D, et al. (2019). Development of a novel NURR1/NOT agonist from hit to lead and candidate for the potential treatment of Parkinson's disease. Bioorg Med Chem Lett, 29:929-932.
[212] Zhang Z, Li X, Xie WJ, Tuo H, Hintermann S, Jankovic J, et al. (2012). Anti-parkinsonian effects of Nurr1 activator in ubiquitin-proteasome system impairment induced animal model of Parkinson's disease. CNS Neurol Disord Drug Targets, 11:768-773.
[213] Ordentlich P, Yan Y, Zhou S, Heyman RA (2003). Identification of the antineoplastic agent 6-mercaptopurine as an activator of the orphan nuclear hormone receptor Nurr1. J Biol Chem, 278:24791-24799.
[214] Kadkhodaei B, Ito T, Joodmardi E, Mattsson B, Rouillard C, Carta M, et al. (2009). Nurr1 is required for maintenance of maturing and adult midbrain dopamine neurons. J Neurosci, 29:15923-15932.
[215] Castillo SO, Baffi JS, Palkovits M, Goldstein DS, Kopin IJ, Witta J, et al. (1998). Dopamine biosynthesis is selectively abolished in substantia nigra/ventral tegmental area but not in hypothalamic neurons in mice with targeted disruption of the Nurr1 gene. Mol Cell Neurosci, 11:36-46.
[216] Skerrett R, Malm T, Landreth G (2014). Nuclear receptors in neurodegenerative diseases. Neurobiol Dis, 72 Pt A:104-116.
[217] Dauer W, Przedborski S (2003). Parkinson's disease: mechanisms and models. Neuron, 39:889-909.
[218] Le WD, Xu P, Jankovic J, Jiang H, Appel SH, Smith RG, et al. (2003). Mutations in NR4A2 associated with familial Parkinson disease. Nat Genet, 33:85-89.
[219] Liu H, Wei L, Tao Q, Deng H, Ming M, Xu P, et al. (2012). Decreased NURR1 and PITX3 gene expression in Chinese patients with Parkinson's disease. Eur J Neurol, 19:870-875.
[220] Montarolo F, Perga S, Martire S, Navone DN, Marchet A, Leotta D, et al. (2016). Altered NR4A Subfamily Gene Expression Level in Peripheral Blood of Parkinson's and Alzheimer's Disease Patients. Neurotox Res, 30:338-344.
[221] Spathis AD, Asvos X, Ziavra D, Karampelas T, Topouzis S, Cournia Z, et al. (2017). Nurr1:RXRalpha heterodimer activation as monotherapy for Parkinson's disease. Proc Natl Acad Sci U S A, 114:3999-4004.
[222] Dong J, Li S, Mo JL, Cai HB, Le WD (2016). Nurr1-Based Therapies for Parkinson's Disease. CNS Neurosci Ther, 22:351-359.
[223] Xie X, Peng L, Zhu J, Zhou Y, Li L, Chen Y, et al. (2017). miR-145-5p/Nurr1/TNF-alpha Signaling-Induced Microglia Activation Regulates Neuron Injury of Acute Cerebral Ischemic/Reperfusion in Rats. Front Mol Neurosci, 10:383.
[224] Bhaskar K, Maphis N, Xu G, Varvel NH, Kokiko-Cochran ON, Weick JP, et al. (2014). Microglial derived tumor necrosis factor-alpha drives Alzheimer's disease-related neuronal cell cycle events. Neurobiol Dis, 62:273-285.
[225] Xing G, Zhang L, Russell S, Post R (2006). Reduction of dopamine-related transcription factors Nurr1 and NGFI-B in the prefrontal cortex in schizophrenia and bipolar disorders. Schizophr Res, 84:36-56.
[226] Weinstein JJ, Chohan MO, Slifstein M, Kegeles LS, Moore H, Abi-Dargham A (2017). Pathway-Specific Dopamine Abnormalities in Schizophrenia. Biol Psychiatry, 81:31-42.
[227] Arredondo C, Gonzalez M, Andres ME, Gysling K (2016). Opposite effects of acute and chronic amphetamine on Nurr1 and NF-kappaB p65 in the rat ventral tegmental area. Brain Res, 1652:14-20.
[228] Leo D, di Porzio U, Racagni G, Riva MA, Fumagalli F, Perrone-Capano C (2007). Chronic cocaine administration modulates the expression of transcription factors involved in midbrain dopaminergic neuron function. Exp Neurol, 203:472-480.
[229] Horvath MC, Kovacs GG, Kovari V, Majtenyi K, Hurd YL, Keller E (2007). Heroin abuse is characterized by discrete mesolimbic dopamine and opioid abnormalities and exaggerated nuclear receptor-related 1 transcriptional decline with age. J Neurosci, 27:13371-13375.
[230] Krasnova IN, Ladenheim B, Hodges AB, Volkow ND, Cadet JL (2011). Chronic methamphetamine administration causes differential regulation of transcription factors in the rat midbrain. PLoS One, 6:e19179.
[231] Luo Y, Wang Y, Kuang SY, Chiang YH, Hoffer B (2010). Decreased level of Nurr1 in heterozygous young adult mice leads to exacerbated acute and long-term toxicity after repeated methamphetamine exposure. PLoS One, 5:e15193.
[232] Guo Y, Luo C, Tu G, Li C, Liu Y, Liu W, et al. (2018). Rhynchophylline Downregulates Phosphorylated cAMP Response Element Binding Protein, Nuclear Receptor-related-1, and Brain-derived Neurotrophic Factor Expression in the Hippocampus of Ketamine-induced Conditioned Place Preference Rats. Pharmacogn Mag, 14:81-86.
[233] Li C, Tu G, Luo C, Guo Y, Fang M, Zhu C, et al. (2018). Effects of rhynchophylline on the hippocampal miRNA expression profile in ketamine-addicted rats. Prog Neuropsychopharmacol Biol Psychiatry.
[234] Perry DC, Kramer JH (2015). Reward processing in neurodegenerative disease. Neurocase, 21:120-133.
[235] Backman C, Perlmann T, Wallen A, Hoffer BJ, Morales M (1999). A selective group of dopaminergic neurons express Nurr1 in the adult mouse brain. Brain Res, 851:125-132.
[236] Katunar MR, Saez T, Brusco A, Antonelli MC (2009). Immunocytochemical expression of dopamine-related transcription factors Pitx3 and Nurr1 in prenatally stressed adult rats. J Neurosci Res, 87:1014-1022.
[237] Juarez Olguin H, Calderon Guzman D, Hernandez Garcia E, Barragan Mejia G (2016). The Role of Dopamine and Its Dysfunction as a Consequence of Oxidative Stress. Oxid Med Cell Longev, 2016:9730467.
[238] Lowe N, Kirley A, Hawi Z, Sham P, Wickham H, Kratochvil CJ, et al. (2004). Joint analysis of the DRD5 marker concludes association with attention-deficit/hyperactivity disorder confined to the predominantly inattentive and combined subtypes. Am J Hum Genet, 74:348-356.
[239] Maher BS, Marazita ML, Ferrell RE, Vanyukov MM (2002). Dopamine system genes and attention deficit hyperactivity disorder: a meta-analysis. Psychiatr Genet, 12:207-215.
[240] Volkow ND, Wang GJ, Kollins SH, Wigal TL, Newcorn JH, Telang F, et al. (2009). Evaluating dopamine reward pathway in ADHD: clinical implications. JAMA, 302:1084-1091.
[241] Vuillermot S, Joodmardi E, Perlmann T, Ogren SO, Feldon J, Meyer U (2012). Prenatal immune activation interacts with genetic Nurr1 deficiency in the development of attentional impairments. J Neurosci, 32:436-451.
[242] Zheng C, Zhou XW, Wang JZ (2016). The dual roles of cytokines in Alzheimer's disease: update on interleukins, TNF-alpha, TGF-beta and IFN-gamma. Transl Neurodegener, 5:7.
[243] Smith KM, Bauer L, Fischer M, Barkley R, Navia BA (2005). Identification and characterization of human NR4A2 polymorphisms in attention deficit hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet, 133B:57-63.
[244] Wulff K, Gatti S, Wettstein JG, Foster RG (2010). Sleep and circadian rhythm disruption in psychiatric and neurodegenerative disease. Nat Rev Neurosci, 11:589-599.
[245] Phan T, Malkani R (2019). Sleep and circadian rhythm disruption and stress intersect in Alzheimer's disease. Neurobiology of Stress, 10:100133.
[246] Musiek ES, Xiong DD, Holtzman DM (2015). Sleep, circadian rhythms, and the pathogenesis of Alzheimer disease. Exp Mol Med, 47:e148.
[247] Chung S, Lee EJ, Yun S, Choe HK, Park SB, Son HJ, et al. (2014). Impact of circadian nuclear receptor REV-ERBalpha on midbrain dopamine production and mood regulation. Cell, 157:858-868.
[248] Bellanti F, Iannelli G, Blonda M, Tamborra R, Villani R, Romano A, et al. (2017). Alterations of Clock Gene RNA Expression in Brain Regions of a Triple Transgenic Model of Alzheimer's Disease. J Alzheimers Dis, 59:615-631.
[1] Xue Yingnan, Zhang Zhenhua, Wen Caiyun, Liu Huiru, Wang Suyuan, Li Jiance, Zhuge Qichuan, Chen Weijian, Ye Qiong. Characterization of Alzheimer’s Disease Using Ultra-high b-values Apparent Diffusion Coefficient and Diffusion Kurtosis Imaging[J]. Aging and disease, 2019, 10(5): 1026-1036.
[2] Yang Chun-Sheng, Guo Ai, Li Yulin, Shi Kaibin, Shi Fu-Dong, Li Minshu. Dl-3-n-butylphthalide Reduces Neurovascular Inflammation and Ischemic Brain Injury in Mice[J]. Aging and disease, 2019, 10(5): 964-976.
[3] Zhou Xiao-Li, Xu Meng-Bei, Jin Ting-Yu, Rong Pei-Qing, Zheng Guo-Qing, Lin Yan. Preclinical Evidence and Possible Mechanisms of Extracts or Compounds from Cistanches for Alzheimer’s Disease[J]. Aging and disease, 2019, 10(5): 1075-1093.
[4] Qing-Qing Tao, Yu-Chao Chen, Zhi-Ying Wu. The role of CD2AP in the Pathogenesis of Alzheimer's Disease[J]. Aging and disease, 2019, 10(4): 901-907.
[5] Xu-Xu Deng, Shan-Shan Li, Feng-Yan Sun. Necrostatin-1 Prevents Necroptosis in Brains after Ischemic Stroke via Inhibition of RIPK1-Mediated RIPK3/MLKL Signaling[J]. Aging and disease, 2019, 10(4): 807-817.
[6] Zhi-Ying Tian, Chun-Yan Wang, Tao Wang, Yan-Chun Li, Zhan-You Wang. Glial S100A6 Degrades β-amyloid Aggregation through Targeting Competition with Zinc Ions[J]. Aging and disease, 2019, 10(4): 756-769.
[7] Takehiko Yamanaka, Yuto Uchida, Keita Sakurai, Daisuke Kato, Masayuki Mizuno, Toyohiro Sato, Yuta Madokoro, Yuko Kondo, Ayuko Suzuki, Yoshino Ueki, Fumiyasu Ishii, Cesar V Borlongan, Noriyuki Matsukawa. Anatomical Links between White Matter Hyperintensity and Medial Temporal Atrophy Reveal Impairment of Executive Functions[J]. Aging and disease, 2019, 10(4): 711-718.
[8] Yu-Sheng Li, Zhi-Hua Yang, Yao Zhang, Jing Yang, Dan-Dan Shang, Shu-Yu Zhang, Jun Wu, Yan Ji, Lu Zhao, Chang-He Shi, Yu-Ming Xu. Two Novel Mutations and a de novo Mutation in PSEN1 in Early-onset Alzheimer’s Disease[J]. Aging and disease, 2019, 10(4): 908-914.
[9] Ya-Ting Chang, Hiroaki Kazui, Manabu Ikeda, Chi-Wei Huang, Shu-Hua Huang, Shih-Wei Hsu, Wen-Neng Chang, Chiung-Chih Chang. Genetic Interaction of APOE and FGF1 is Associated with Memory Impairment and Hippocampal Atrophy in Alzheimer’s Disease[J]. Aging and disease, 2019, 10(3): 510-519.
[10] Rongrong Han, Zeyue Liu, Nannan Sun, Shu Liu, Lanlan Li, Yan Shen, Jianbo Xiu, Qi Xu. BDNF Alleviates Neuroinflammation in the Hippocampus of Type 1 Diabetic Mice via Blocking the Aberrant HMGB1/RAGE/NF-κB Pathway[J]. Aging and disease, 2019, 10(3): 611-625.
[11] Kunyu Li, Jiatong Li, Jialin Zheng, Song Qin. Reactive Astrocytes in Neurodegenerative Diseases[J]. Aging and disease, 2019, 10(3): 664-675.
[12] Ashok K. Shetty, Raghavendra Upadhya, Leelavathi N. Madhu, Maheedhar Kodali. Novel Insights on Systemic and Brain Aging, Stroke, Amyotrophic Lateral Sclerosis, and Alzheimer’s Disease[J]. Aging and disease, 2019, 10(2): 470-482.
[13] Saumyendra N. Sarkar, Ashley E. Russell, Elizabeth B. Engler-Chiurazzi, Keyana N. Porter, James W. Simpkins. MicroRNAs and the Genetic Nexus of Brain Aging, Neuroinflammation, Neurodegeneration, and Brain Trauma[J]. Aging and disease, 2019, 10(2): 329-352.
[14] Christopher Bi, Stephanie Bi, Bin Li. Processing of Mutant β-Amyloid Precursor Protein and the Clinicopathological Features of Familial Alzheimer’s Disease[J]. Aging and disease, 2019, 10(2): 383-403.
[15] Seong Gak Jeon, Eun Ji Song, Dongje Lee, Junyong Park, Yunkwon Nam, Jin-il Kim, Minho Moon. Traditional Oriental Medicines and Alzheimer’s Disease[J]. Aging and disease, 2019, 10(2): 307-328.
Viewed
Full text


Abstract

Cited

  Shared   
Copyright © 2014 Aging and Disease, All Rights Reserved.
Address: Aging and Disease Editorial Office 3400 Camp Bowie Boulevard Fort Worth, TX76106 USA
Fax: (817) 735-0408 E-mail: editorial@aginganddisease.org
Powered by Beijing Magtech Co. Ltd