1932

Abstract

Neurodegenerative diseases are characterized by a progressive loss of neurons that leads to a broad range of disabilities, including severe cognitive decline and motor impairment, for which there are no effective therapies. Several lines of evidence support a putative therapeutic role of nuclear receptors (NRs) in these types of disorders. NRs are ligand-activated transcription factors that regulate the expression of a wide range of genes linked to metabolism and inflammation. Although the activation of NRs in animal models of neurodegenerative disease exhibits promising results, the translation of this strategy to clinical practice has been unsuccessful. In this review we discuss the role of NRs in neurodegenerative diseases in light of preclinical and clinical studies, as well as new findings derived from the analysis of transcriptomic databases from humans and animal models. We discuss the failure in the translation of NR-based therapeutic approaches and consider alternative and novel research avenues in the development of effective therapies for neurodegenerative diseases.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-pharmtox-010818-021807
2019-01-06
2024-04-14
Loading full text...

Full text loading...

/deliver/fulltext/pharmtox/59/1/annurev-pharmtox-010818-021807.html?itemId=/content/journals/10.1146/annurev-pharmtox-010818-021807&mimeType=html&fmt=ahah

Literature Cited

  1. 1.  Wood LB, Winslow AR, Strasser SD 2015. Systems biology of neurodegenerative diseases. Integr. Biol. 7:758–75
    [Google Scholar]
  2. 2.  Saijo K, Crotti A, Glass CK 2010. Nuclear receptors, inflammation, and neurodegenerative diseases. Adv. Immunol. 106:21–59
    [Google Scholar]
  3. 3.  Skerrett R, Malm T, Landreth G 2014. Nuclear receptors in neurodegenerative diseases. Neurobiol. Dis. 72:Pt. A104–16
    [Google Scholar]
  4. 4.  Evans RM, Mangelsdorf DJ 2014. Nuclear receptors, RXR, and the Big Bang. Cell 157:255–66
    [Google Scholar]
  5. 5.  Musiek ES, Holtzman DM 2015. Three dimensions of the amyloid hypothesis: time, space and ‘wingmen’. Nat. Neurosci. 18:800–6
    [Google Scholar]
  6. 6.  Chow VW, Mattson MP, Wong PC, Gleichmann M 2010. An overview of APP processing enzymes and products. Neuromolecular Med 12:1–12
    [Google Scholar]
  7. 7.  Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T et al. 2010. Decreased clearance of CNS β-amyloid in Alzheimer's disease. Science 330:1774
    [Google Scholar]
  8. 8.  Klein C, Westenberger A 2012. Genetics of Parkinson's disease. Cold Spring Harb. Perspect. Med. 2:a008888
    [Google Scholar]
  9. 9.  Stefanis L 2012. α-Synuclein in Parkinson's disease. Cold Spring Harb. Perspect. Med. 2:a009399
    [Google Scholar]
  10. 10.  Dauer W, Przedborski S 2003. Parkinson's disease: mechanisms and models. Neuron 39:889–909
    [Google Scholar]
  11. 11.  Nolan YM, Sullivan AM, Toulouse A 2013. Parkinson's disease in the nuclear age of neuroinflammation. Trends Mol. Med. 19:187–96
    [Google Scholar]
  12. 12.  Saudou F, Humbert S 2016. The biology of Huntingtin. Neuron 89:910–26
    [Google Scholar]
  13. 13.  Landles C, Bates GP 2004. Huntingtin and the molecular pathogenesis of Huntington's disease. EMBO Rep 5:958–63
    [Google Scholar]
  14. 14.  Ajroud-Driss S, Siddique T 2015. Sporadic and hereditary amyotrophic lateral sclerosis (ALS). Biochim. Biophys. Acta 1852:679–84
    [Google Scholar]
  15. 15.  Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A et al. 2011. Amyotrophic lateral sclerosis. Lancet 377:942–55
    [Google Scholar]
  16. 16.  Sever R, Glass CK 2013. Signaling by nuclear receptors. Cold Spring Harb. Perspect. Biol. 5:a016709
    [Google Scholar]
  17. 17.  Dawson MI, Xia Z 2012. The retinoid X receptors and their ligands. Biochim. Biophys. Acta 1821:21–56
    [Google Scholar]
  18. 18.  Lammi J, Perlmann T, Aarnisalo P 2008. Corepressor interaction differentiates the permissive and non-permissive retinoid X receptor heterodimers. Arch. Biochem. Biophys. 472:105–14
    [Google Scholar]
  19. 19.  Glass CK, Saijo K 2010. Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells. Nat. Rev. Immunol. 10:365–76
    [Google Scholar]
  20. 20.  Saijo K, Winner B, Carson CT, Collier JG, Boyer L et al. 2009. A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death. Cell 137:47–59
    [Google Scholar]
  21. 21.  Krezel W, Kastner P, Chambon P 1999. Differential expression of retinoid receptors in the adult mouse central nervous system. Neuroscience 89:1291–300
    [Google Scholar]
  22. 22.  Arfaoui A, Lobo MV, Boulbaroud S, Ouichou A, Mesfioui A, Arenas MI 2013. Expression of retinoic acid receptors and retinoid X receptors in normal and vitamin A deficient adult rat brain. Ann. Anat. 195:111–21
    [Google Scholar]
  23. 23.  Desvergne B 2007. RXR: from partnership to leadership in metabolic regulations. Vitam. Horm. 75:1–32
    [Google Scholar]
  24. 24.  Ruhl R, Krzyzosiak A, Niewiadomska-Cimicka A, Rochel N, Szeles L et al. 2015. 9-cis-13,14-dihydroretinoic acid is an endogenous retinoid acting as RXR ligand in mice. PLOS Genet 11:e1005213
    [Google Scholar]
  25. 25.  Lane MA, Bailey SJ 2005. Role of retinoid signaling in the adult brain. Prog. Neurobiol. 75:275–93
    [Google Scholar]
  26. 26.  Chiang MY, Misner D, Kempermann G, Schikorski T, Giguere V et al. 1998. An essential role for retinoid receptors RARβ and RXRγ in long-term potentiation and depression. Neuron 21:1353–61
    [Google Scholar]
  27. 27.  Sarti F, Schroeder J, Aoto J, Chen L 2012. Conditional RARα knockout mice reveal acute requirement for retinoic acid and RARα in homeostatic plasticity. Front. Mol. Neurosci. 5:16
    [Google Scholar]
  28. 28.  Ransom J, Morgan PJ, McCaffery PJ, Stoney PN 2014. The rhythm of retinoids in the brain. J. Neurochem. 129:366–76
    [Google Scholar]
  29. 29.  Whitney KD, Watson MA, Collins JL, Benson WG, Stone TM et al. 2002. Regulation of cholesterol homeostasis by the liver X receptors in the central nervous system. Mol. Endocrinol. 16:1378–85
    [Google Scholar]
  30. 30.  Wang L, Schuster GU, Hultenby K, Zhang Q, Andersson S, Gustafsson JA 2002. Liver X receptors in the central nervous system: from lipid homeostasis to neuronal degeneration. PNAS 99:13878–83
    [Google Scholar]
  31. 31.  Andersson S, Gustafsson N, Warner M, Gustafsson JA 2005. Inactivation of liver X receptor β leads to adult-onset motor neuron degeneration in male mice. PNAS 102:3857–62
    [Google Scholar]
  32. 32.  Warden A, Truitt J, Merriman M, Ponomareva O, Jameson K et al. 2016. Localization of PPAR isotypes in the adult mouse and human brain. Sci. Rep. 6:27618
    [Google Scholar]
  33. 33.  Wahli W, Michalik L 2012. PPARs at the crossroads of lipid signaling and inflammation. Trends Endocrinol. Metab. 23:351–63
    [Google Scholar]
  34. 34.  Kapadia R, Yi JH, Vemuganti R 2008. Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-γ agonists. Front. Biosci. 13:1813–26
    [Google Scholar]
  35. 35.  Quintanilla RA, Utreras E, Cabezas-Opazo FA 2014. Role of PPAR γ in the differentiation and function of neurons. PPAR Res 2014:768594
    [Google Scholar]
  36. 36.  Fidaleo M, Fanelli F, Ceru MP, Moreno S 2014. Neuroprotective properties of peroxisome proliferator-activated receptor alpha (PPARα) and its lipid ligands. Curr. Med. Chem. 21:2803–21
    [Google Scholar]
  37. 37.  Chakravarthy MV, Zhu Y, Lopez M, Yin L, Wozniak DF et al. 2007. Brain fatty acid synthase activates PPARα to maintain energy homeostasis. J. Clin. Investig. 117:2539–52
    [Google Scholar]
  38. 38.  Roy A, Jana M, Kundu M, Corbett GT, Rangaswamy SB et al. 2015. HMG-CoA reductase inhibitors bind to PPARα to upregulate neurotrophin expression in the brain and improve memory in mice. Cell Metab 22:253–65
    [Google Scholar]
  39. 39.  Hall MG, Quignodon L, Desvergne B 2008. Peroxisome proliferator-activated receptor β/δ in the brain: facts and hypothesis. PPAR Res 2008:780452
    [Google Scholar]
  40. 40.  Decressac M, Volakakis N, Bjorklund A, Perlmann T 2013. NURR1 in Parkinson disease—from pathogenesis to therapeutic potential. Nat. Rev. Neurol. 9:629–36
    [Google Scholar]
  41. 41.  Law SW, Conneely OM, DeMayo FJ, O'Malley BW 1992. Identification of a new brain-specific transcription factor, NURR1. Mol. Endocrinol. 6:2129–35
    [Google Scholar]
  42. 42.  Zetterstrom RH, Solomin L, Jansson L, Hoffer BJ, Olson L, Perlmann T 1997. Dopamine neuron agenesis in Nurr1-deficient mice. Science 276:248–50
    [Google Scholar]
  43. 43.  Jiang C, Wan X, He Y, Pan T, Jankovic J, Le W 2005. Age-dependent dopaminergic dysfunction in Nurr1 knockout mice. Exp. Neurol. 191:154–62
    [Google Scholar]
  44. 44.  Kadkhodaei B, Ito T, Joodmardi E, Mattsson B, Rouillard C et al. 2009. Nurr1 is required for maintenance of maturing and adult midbrain dopamine neurons. J. Neurosci. 29:15923–32
    [Google Scholar]
  45. 45.  McFarland K, Spalding TA, Hubbard D, Ma JN, Olsson R, Burstein ES 2013. Low dose bexarotene treatment rescues dopamine neurons and restores behavioral function in models of Parkinson's disease. ACS Chem. Neurosci. 4:1430–38
    [Google Scholar]
  46. 46.  Akram A, Schmeidler J, Katsel P, Hof PR, Haroutunian V 2010. Increased expression of RXRα in dementia: an early harbinger for the cholesterol dyshomeostasis?. Mol. Neurodegener. 5:36
    [Google Scholar]
  47. 47.  Cramer PE, Cirrito JR, Wesson DW, Lee CY, Karlo JC et al. 2012. ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models. Science 335:1503–6
    [Google Scholar]
  48. 48.  Tesseur I, De Strooper B 2013. When the dust settles: What did we learn from the bexarotene discussion?. Alzheimers Res. Ther. 5:54
    [Google Scholar]
  49. 49.  Moutinho M, Landreth GE 2017. Therapeutic potential of nuclear receptor agonists in Alzheimer's disease. J. Lipid Res. 58:1937–49
    [Google Scholar]
  50. 50.  Jiang Q, Lee CY, Mandrekar S, Wilkinson B, Cramer P et al. 2008. ApoE promotes the proteolytic degradation of Aβ. Neuron 58:681–93
    [Google Scholar]
  51. 51.  Savage JC, Jay T, Goduni E, Quigley C, Mariani MM et al. 2015. Nuclear receptors license phagocytosis by trem2+ myeloid cells in mouse models of Alzheimer's disease. J. Neurosci. 35:6532–43
    [Google Scholar]
  52. 52.  Yamanaka M, Ishikawa T, Griep A, Axt D, Kummer MP, Heneka MT 2012. PPARγ/RXRα-induced and CD36-mediated microglial amyloid-βphagocytosis results in cognitive improvement in amyloid precursor protein/presenilin 1 mice. J. Neurosci. 32:17321–31
    [Google Scholar]
  53. 53.  Mariani MM, Malm T, Lamb R, Jay TR, Neilson L et al. 2017. Neuronally-directed effects of RXR activation in a mouse model of Alzheimer's disease. Sci. Rep. 7:42270
    [Google Scholar]
  54. 54.  Ghosal K, Haag M, Verghese PB, West T, Veenstra T et al. 2016. A randomized controlled study to evaluate the effect of bexarotene on amyloid-β and apolipoprotein E metabolism in healthy subjects. Alzheimers Dement 2:110–20
    [Google Scholar]
  55. 55.  Cummings JL, Zhong K, Kinney JW, Heaney C, Moll-Tudla J et al. 2016. Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer's disease. Alzheimers Res. Ther. 8:4
    [Google Scholar]
  56. 56.  Volakakis N, Tiklova K, Decressac M, Papathanou M, Mattsson B et al. 2015. Nurr1 and retinoid X receptor ligands stimulate Ret signaling in dopamine neurons and can alleviate α-synuclein disrupted gene expression. J. Neurosci. 35:14370–85
    [Google Scholar]
  57. 57.  Spathis AD, Asvos X, Ziavra D, Karampelas T, Topouzis S et al. 2017. Nurr1:RXRα heterodimer activation as monotherapy for Parkinson's disease. PNAS 114:3999–4004
    [Google Scholar]
  58. 58.  Wang J, Bi W, Zhao W, Varghese M, Koch RJ et al. 2016. Selective brain penetrable Nurr1 transactivator for treating Parkinson's disease. Oncotarget 7:7469–79
    [Google Scholar]
  59. 59.  Dickey AS, Sanchez DN, Arreola M, Sampat KR, Fan W et al. 2017. PPARδ activation by bexarotene promotes neuroprotection by restoring bioenergetic and quality control homeostasis. Sci. Transl. Med. 9:419eaal2332
    [Google Scholar]
  60. 60.  Dickey AS, Pineda VV, Tsunemi T, Liu PP, Miranda HC et al. 2016. PPAR-δ is repressed in Huntington's disease, is required for normal neuronal function and can be targeted therapeutically. Nat. Med. 22:37–45
    [Google Scholar]
  61. 61.  Riancho J, Ruiz-Soto M, Berciano MT, Berciano J, Lafarga M 2015. Neuroprotective effect of bexarotene in the SOD1G93A mouse model of amyotrophic lateral sclerosis. Front. Cell. Neurosci. 9:250
    [Google Scholar]
  62. 62.  Goncalves MB, Clarke E, Hobbs C, Malmqvist T, Deacon R et al. 2013. Amyloid βinhibits retinoic acid synthesis exacerbating Alzheimer disease pathology which can be attenuated by an retinoic acid receptor αagonist. Eur. J. Neurosci. 37:1182–92
    [Google Scholar]
  63. 63.  Zeng J, Chen L, Wang Z, Chen Q, Fan Z et al. 2017. Marginal vitamin A deficiency facilitates Alzheimer's pathogenesis. Acta Neuropathol 133:967–82
    [Google Scholar]
  64. 64.  Reinhardt S, Grimm MO, Stahlmann C, Hartmann T, Shudo K et al. 2016. Rescue of hypovitaminosis A induces non-amyloidogenic amyloid precursor protein (APP) processing. Curr. Alzheimer Res. 13:1277–89
    [Google Scholar]
  65. 65.  Goodman AB, Pardee AB 2003. Evidence for defective retinoid transport and function in late onset Alzheimer's disease. PNAS 100:2901–5
    [Google Scholar]
  66. 66.  Kawahara K, Nishi K, Suenobu M, Ohtsuka H, Maeda A et al. 2009. Oral administration of synthetic retinoid Am80 (tamibarotene) decreases brain β-amyloid peptides in APP23 mice. Biol. Pharm. Bull. 32:1307–9
    [Google Scholar]
  67. 67.  Kawahara K, Suenobu M, Ohtsuka H, Kuniyasu A, Sugimoto Y et al. 2014. Cooperative therapeutic action of retinoic acid receptor and retinoid X receptor agonists in a mouse model of Alzheimer's disease. J. Alzheimers Dis. 42:587–605
    [Google Scholar]
  68. 68.  Fukasawa H, Nakagomi M, Yamagata N, Katsuki H, Kawahara K et al. 2012. Tamibarotene: a candidate retinoid drug for Alzheimer's disease. Biol. Pharm. Bull. 35:1206–12
    [Google Scholar]
  69. 69.  Endres K, Fahrenholz F, Lotz J, Hiemke C, Teipel S et al. 2014. Increased CSF APPs-α levels in patients with Alzheimer disease treated with acitretin. Neurology 83:1930–35
    [Google Scholar]
  70. 70.  Esteves M, Cristovao AC, Saraiva T, Rocha SM, Baltazar G et al. 2015. Retinoic acid-loaded polymeric nanoparticles induce neuroprotection in a mouse model for Parkinson's disease. Front. Aging Neurosci. 7:20
    [Google Scholar]
  71. 71.  Yin LH, Shen H, Diaz-Ruiz O, Backman CM, Bae E et al. 2012. Early post-treatment with 9-cis retinoic acid reduces neurodegeneration of dopaminergic neurons in a rat model of Parkinson's disease. BMC Neurosci 13:120
    [Google Scholar]
  72. 72.  Katsuki H, Kurimoto E, Takemori S, Kurauchi Y, Hisatsune A et al. 2009. Retinoic acid receptor stimulation protects midbrain dopaminergic neurons from inflammatory degeneration via BDNF-mediated signaling. J. Neurochem. 110:707–18
    [Google Scholar]
  73. 73.  Hodges A, Strand AD, Aragaki AK, Kuhn A, Sengstag T et al. 2006. Regional and cellular gene expression changes in human Huntington's disease brain. Hum. Mol. Genet. 15:965–77
    [Google Scholar]
  74. 74.  Niewiadomska-Cimicka A, Krzyzosiak A, Ye T, Podlesny-Drabiniok A, Dembele D et al. 2017. Genome-wide analysis of RARβ transcriptional targets in mouse striatum links retinoic acid signaling with Huntington's disease and other neurodegenerative disorders. Mol. Neurobiol. 54:3859–78
    [Google Scholar]
  75. 75.  Kolarcik CL, Bowser R 2012. Retinoid signaling alterations in amyotrophic lateral sclerosis. Am. J. Neurodegener. Dis. 1:130–45
    [Google Scholar]
  76. 76.  Corcoran J, So PL, Maden M 2002. Absence of retinoids can induce motoneuron disease in the adult rat and a retinoid defect is present in motoneuron disease patients. J. Cell Sci. 115:4735–41
    [Google Scholar]
  77. 77.  Crochemore C, Virgili M, Bonamassa B, Canistro D, Pena-Altamira E et al. 2009. Long-term dietary administration of valproic acid does not affect, while retinoic acid decreases, the lifespan of G93A mice, a model for amyotrophic lateral sclerosis. Muscle Nerve 39:548–52
    [Google Scholar]
  78. 78.  Levine TD, Bowser R, Hank NC, Gately S, Stephan D et al. 2012. A pilot trial of pioglitazone HCl and tretinoin in ALS: cerebrospinal fluid biomarkers to monitor drug efficacy and predict rate of disease progression. Neurol. Res. Int. 2012:582075
    [Google Scholar]
  79. 79.  Spann NJ, Garmire LX, McDonald JG, Myers DS, Milne SB et al. 2012. Regulated accumulation of desmosterol integrates macrophage lipid metabolism and inflammatory responses. Cell 151:138–52
    [Google Scholar]
  80. 80.  Sandoval-Hernandez AG, Restrepo A, Cardona-Gomez GP, Arboleda G 2016. LXR activation protects hippocampal microvasculature in very old triple transgenic mouse model of Alzheimer's disease. Neurosci. Lett. 621:15–21
    [Google Scholar]
  81. 81.  Lee JH, Park SM, Kim OS, Lee CS, Woo JH et al. 2009. Differential SUMOylation of LXRα and LXRβ mediates transrepression of STAT1 inflammatory signaling in IFN-γ-stimulated brain astrocytes. Mol. Cell 35:806–17
    [Google Scholar]
  82. 82.  Cheng D, Kim WS, Garner B 2008. Regulation of α-synuclein expression by liver X receptor ligands in vitro. Neuroreport 19:1685–89
    [Google Scholar]
  83. 83.  Marwarha G, Rhen T, Schommer T, Ghribi O 2011. The oxysterol 27-hydroxycholesterol regulates α-synuclein and tyrosine hydroxylase expression levels in human neuroblastoma cells through modulation of liver X receptors and estrogen receptors—relevance to Parkinson's disease. J. Neurochem. 119:1119–36
    [Google Scholar]
  84. 84.  Rantham Prabhakara JP, Feist G, Thomasson S, Thompson A, Schommer E, Ghribi O 2008. Differential effects of 24-hydroxycholesterol and 27-hydroxycholesterol on tyrosine hydroxylase and α-synuclein in human neuroblastoma SH-SY5Y cells. J. Neurochem. 107:1722–29
    [Google Scholar]
  85. 85.  Dai YB, Tan XJ, Wu WF, Warner M, Gustafsson JA 2012. Liver X receptor β protects dopaminergic neurons in a mouse model of Parkinson disease. PNAS 109:13112–17
    [Google Scholar]
  86. 86.  Futter M, Diekmann H, Schoenmakers E, Sadiq O, Chatterjee K, Rubinsztein DC 2009. Wild-type but not mutant huntingtin modulates the transcriptional activity of liver X receptors. J. Med. Genet. 46:438–46
    [Google Scholar]
  87. 87.  Valenza M, Leoni V, Karasinska JM, Petricca L, Fan J et al. 2010. Cholesterol defect is marked across multiple rodent models of Huntington's disease and is manifest in astrocytes. J. Neurosci. 30:10844–50
    [Google Scholar]
  88. 88.  Valenza M, Marullo M, Di Paolo E, Cesana E, Zuccato C et al. 2015. Disruption of astrocyte-neuron cholesterol cross talk affects neuronal function in Huntington's disease. Cell Death Differ 22:690–702
    [Google Scholar]
  89. 89.  Abildayeva K, Jansen PJ, Hirsch-Reinshagen V, Bloks VW, Bakker AH et al. 2006. 24: (. S )-hydroxycholesterol participates in a liver X receptor-controlled pathway in astrocytes that regulates apolipoprotein E-mediated cholesterol efflux. J. Biol. Chem. 281:12799–808
    [Google Scholar]
  90. 90.  Valenza M, Chen JY, Di Paolo E, Ruozi B, Belletti D et al. 2015. Cholesterol-loaded nanoparticles ameliorate synaptic and cognitive function in Huntington's disease mice. EMBO Mol. Med. 7:1547–64
    [Google Scholar]
  91. 91.  Chen JY, Tran C, Hwang L, Deng G, Jung ME et al. 2016. Partial amelioration of peripheral and central symptoms of Huntington's disease via modulation of lipid metabolism. J. Huntingtons Dis. 5:65–81
    [Google Scholar]
  92. 92.  Kim SM, Noh MY, Kim H, Cheon SY, Lee KM et al. 2017. 25-Hydroxycholesterol is involved in the pathogenesis of amyotrophic lateral sclerosis. Oncotarget 8:11855–67
    [Google Scholar]
  93. 93.  Bigini P, Steffensen KR, Ferrario A, Diomede L, Ferrara G et al. 2010. Neuropathologic and biochemical changes during disease progression in liver X receptor β−/− mice, a model of adult neuron disease. J. Neuropathol. Exp. Neurol. 69:593–605
    [Google Scholar]
  94. 94.  de la Monte SM, Wands JR 2006. Molecular indices of oxidative stress and mitochondrial dysfunction occur early and often progress with severity of Alzheimer's disease. J. Alzheimer's Dis. 9:167–81
    [Google Scholar]
  95. 95.  Snowden SG, Ebshiana AA, Hye A, An Y, Pletnikova O et al. 2017. Association between fatty acid metabolism in the brain and Alzheimer disease neuropathology and cognitive performance: a nontargeted metabolomic study. PLOS Med 14:e1002266
    [Google Scholar]
  96. 96.  Zhao Y, Calon F, Julien C, Winkler JW, Petasis NA et al. 2011. Docosahexaenoic acid-derived neuroprotectin D1 induces neuronal survival via secretase- and PPARγ-mediated mechanisms in Alzheimer's disease models. PLOS ONE 6:e15816
    [Google Scholar]
  97. 97.  Lim GP, Calon F, Morihara T, Yang F, Teter B et al. 2005. A diet enriched with the omega-3 fatty acid docosahexaenoic acid reduces amyloid burden in an aged Alzheimer mouse model. J. Neurosci. 25:3032–40
    [Google Scholar]
  98. 98.  Morris MC, Evans DA, Bienias JL, Tangney CC, Bennett DA et al. 2003. Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease. Arch. Neurol. 60:940–46
    [Google Scholar]
  99. 99.  Kummer MP, Heneka MT 2008. PPARs in Alzheimer's disease. PPAR Res 2008:403896
    [Google Scholar]
  100. 100.  Heneka MT, Fink A, Doblhammer G 2015. Effect of pioglitazone medication on the incidence of dementia. Ann. Neurol. 78:284–94
    [Google Scholar]
  101. 101.  Heneka MT, Reyes-Irisarri E, Hull M, Kummer MP 2011. Impact and therapeutic potential of PPARs in Alzheimer's disease. Curr. Neuropharmacol. 9:643–50
    [Google Scholar]
  102. 102.  Badhwar A, Brown R, Stanimirovic DB, Haqqani AS, Hamel E 2017. Proteomic differences in brain vessels of Alzheimer's disease mice: normalization by PPARγ agonist pioglitazone. J. Cereb. Blood Flow Metab. 37:1120–36
    [Google Scholar]
  103. 103.  Harrington C, Sawchak S, Chiang C, Davies J, Donovan C et al. 2011. Rosiglitazone does not improve cognition or global function when used as adjunctive therapy to AChE inhibitors in mild-to-moderate Alzheimer's disease: two phase 3 studies. Curr. Alzheimer Res. 8:592–606
    [Google Scholar]
  104. 104.  Gold M, Alderton C, Zvartau-Hind M, Egginton S, Saunders AM et al. 2010. Rosiglitazone monotherapy in mild-to-moderate Alzheimer's disease: results from a randomized, double-blind, placebo-controlled phase III study. Dement. Geriatr. Cogn. Disord. 30:131–46
    [Google Scholar]
  105. 105.  Yakunin E, Kisos H, Kulik W, Grigoletto J, Wanders RJ, Sharon R 2014. The regulation of catalase activity by PPAR γ is affected by α-synuclein. Ann. Clin. Transl. Neurol. 1:145–59
    [Google Scholar]
  106. 106.  Brauer R, Bhaskaran K, Chaturvedi N, Dexter DT, Smeeth L, Douglas I 2015. Glitazone treatment and incidence of Parkinson's disease among people with diabetes: a retrospective cohort study. PLOS Med 12:e1001854
    [Google Scholar]
  107. 107.  Corona JC, Duchen MR 2015. PPARγ and PGC-1α as therapeutic targets in Parkinson's. Neurochem. Res. 40:308–16
    [Google Scholar]
  108. 108.  Carta AR 2013. PPAR-γ: therapeutic prospects in Parkinson's disease. Curr. Drug Targets 14:743–51
    [Google Scholar]
  109. 109.  Barbiero JK, Santiago RM, Persike DS, da Silva Fernandes MJ, Tonin FS et al. 2014. Neuroprotective effects of peroxisome proliferator-activated receptor alpha and gamma agonists in model of parkinsonism induced by intranigral 1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine. Behav. Brain Res. 274:390–99
    [Google Scholar]
  110. 110.  Martin HL, Mounsey RB, Sathe K, Mustafa S, Nelson MC et al. 2013. A peroxisome proliferator-activated receptor-δ agonist provides neuroprotection in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease. Neuroscience 240:191–203
    [Google Scholar]
  111. 111.  Chaturvedi RK, Beal MF 2008. PPAR: a therapeutic target in Parkinson's disease. J. Neurochem. 106:506–18
    [Google Scholar]
  112. 112.  Bonato JM, Bassani TB, Milani H, Vital M, de Oliveira RMW 2018. Pioglitazone reduces mortality, prevents depressive-like behavior, and impacts hippocampal neurogenesis in the 6-OHDA model of Parkinson's disease in rats. Exp. Neurol. 300:188–200
    [Google Scholar]
  113. 113.  Jung TW, Lee JY, Shim WS, Kang ES, Kim SK et al. 2007. Rosiglitazone protects human neuroblastoma SH-SY5Y cells against MPP+ induced cytotoxicity via inhibition of mitochondrial dysfunction and ROS production. J. Neurol. Sci. 253:53–60
    [Google Scholar]
  114. 114. NINDS Exploratory Trials in Parkinson Disease (NET-PD) FS-ZONE Investigators. 2015. Pioglitazone in early Parkinson's disease: a phase 2, multicentre, double-blind, randomised trial. Lancet. Neurol. 14:795–803
    [Google Scholar]
  115. 115.  Johri A, Calingasan NY, Hennessey TM, Sharma A, Yang L et al. 2012. Pharmacologic activation of mitochondrial biogenesis exerts widespread beneficial effects in a transgenic mouse model of Huntington's disease. Hum. Mol. Genet. 21:1124–37
    [Google Scholar]
  116. 116.  Chiang MC, Chen CM, Lee MR, Chen HW, Chen HM et al. 2010. Modulation of energy deficiency in Huntington's disease via activation of the peroxisome proliferator-activated receptor γ. Hum. Mol. Genet. 19:4043–58
    [Google Scholar]
  117. 117.  Jin J, Albertz J, Guo Z, Peng Q, Rudow G et al. 2013. Neuroprotective effects of PPAR-γ agonist rosiglitazone in N171-82Q mouse model of Huntington's disease. J. Neurochem. 125:410–19
    [Google Scholar]
  118. 118.  Chiang MC, Chern Y, Huang RN 2012. PPARγ rescue of the mitochondrial dysfunction in Huntington's disease. Neurobiol. Dis. 45:322–28
    [Google Scholar]
  119. 119.  Veldink JH, Kalmijn S, Groeneveld GJ, Wunderink W, Koster A et al. 2007. Intake of polyunsaturated fatty acids and vitamin E reduces the risk of developing amyotrophic lateral sclerosis. J. Neurol. Neurosurg. Psychiatry 78:367–71
    [Google Scholar]
  120. 120.  Fitzgerald KC, O'Reilly EJ, Falcone GJ, McCullough ML, Park Y et al. 2014. Dietary ω -3 polyunsaturated fatty acid intake and risk for amyotrophic lateral sclerosis. JAMA Neurol 71:1102–10
    [Google Scholar]
  121. 121.  Kiaei M, Kipiani K, Chen J, Calingasan NY, Beal MF 2005. Peroxisome proliferator-activated receptor-γ agonist extends survival in transgenic mouse model of amyotrophic lateral sclerosis. Exp. Neurol. 191:331–36
    [Google Scholar]
  122. 122.  Schutz B, Reimann J, Dumitrescu-Ozimek L, Kappes-Horn K, Landreth GE et al. 2005. The oral antidiabetic pioglitazone protects from neurodegeneration and amyotrophic lateral sclerosis-like symptoms in superoxide dismutase-G93A transgenic mice. J. Neurosci. 25:7805–12
    [Google Scholar]
  123. 123.  Joardar A, Menzl J, Podolsky TC, Manzo E, Estes PS et al. 2015. PPAR gamma activation is neuroprotective in a Drosophila model of ALS based on TDP-43. Hum. Mol. Genet. 24:1741–54
    [Google Scholar]
  124. 124.  Benedusi V, Martorana F, Brambilla L, Maggi A, Rossi D 2012. The peroxisome proliferator-activated receptor γ (PPARγ) controls natural protective mechanisms against lipid peroxidation in amyotrophic lateral sclerosis. J. Biol. Chem. 287:35899–911
    [Google Scholar]
  125. 125.  Esmaeili MA, Yadav S, Gupta RK, Waggoner GR, Deloach A et al. 2016. Preferential PPAR-α activation reduces neuroinflammation, and blocks neurodegeneration in vivo. Hum. Mol. Genet. 25:317–27
    [Google Scholar]
  126. 126.  Dupuis L, Dengler R, Heneka MT, Meyer T, Zierz S et al. 2012. A randomized, double blind, placebo-controlled trial of pioglitazone in combination with riluzole in amyotrophic lateral sclerosis. PLOS ONE 7:e37885
    [Google Scholar]
  127. 127.  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
    [Google Scholar]
  128. 128.  Kim CH, Han BS, Moon J, Kim DJ, Shin J et al. 2015. Nuclear receptor Nurr1 agonists enhance its dual functions and improve behavioral deficits in an animal model of Parkinson's disease. PNAS 112:8756–61
    [Google Scholar]
  129. 129.  Shaw N, Elholm M, Noy N 2003. Retinoic acid is a high affinity selective ligand for the peroxisome proliferator-activated receptor β/δ. J. Biol. Chem. 278:41589–92
    [Google Scholar]
  130. 130.  Dong J, Li S, Mo JL, Cai HB, Le WD 2016. Nurr1-based therapies for Parkinson's disease. CNS Neurosci. Ther. 22:351–59
    [Google Scholar]
  131. 131.  Costet P, Lalanne F, Gerbod-Giannone MC, Molina JR, Fu X et al. 2003. Retinoic acid receptor-mediated induction of ABCA1 in macrophages. Mol. Cell. Biol. 23:7756–66
    [Google Scholar]
  132. 132.  Tippmann F, Hundt J, Schneider A, Endres K, Fahrenholz F 2009. Up-regulation of the α-secretase ADAM10 by retinoic acid receptors and acitretin. FASEB J 23:1643–54
    [Google Scholar]
  133. 133.  Geldmacher DS, Fritsch T, McClendon MJ, Landreth G 2011. A randomized pilot clinical trial of the safety of pioglitazone in treatment of patients with Alzheimer disease. Arch. Neurol. 68:45–50
    [Google Scholar]
  134. 134.  Bagheri M, Joghataei MT, Mohseni S, Roghani M 2011. Genistein ameliorates learning and memory deficits in amyloid β(1–40) rat model of Alzheimer's disease. Neurobiol. Learn. Mem. 95:270–76
    [Google Scholar]
  135. 135.  Zaman Z, Roche S, Fielden P, Frost PG, Niriella DC, Cayley AC 1992. Plasma concentrations of vitamins A and E and carotenoids in Alzheimer's disease. Age Ageing 21:91–94
    [Google Scholar]
  136. 136.  Hargis KE, Blalock EM 2017. Transcriptional signatures of brain aging and Alzheimer's disease: What are our rodent models telling us?. Behav. Brain Res. 322:311–28
    [Google Scholar]
  137. 137.  Liang WS, Dunckley T, Beach TG, Grover A, Mastroeni D et al. 2010. Neuronal gene expression in non-demented individuals with intermediate Alzheimer's disease neuropathology. Neurobiol. Aging 31:549–66
    [Google Scholar]
  138. 138.  Jeandel C, Nicolas MB, Dubois F, Nabet-Belleville F, Penin F, Cuny G 1989. Lipid peroxidation and free radical scavengers in Alzheimer's disease. Gerontology 35:275–82
    [Google Scholar]
  139. 139.  Jimenez-Jimenez FJ, Molina JA, de Bustos F, Orti-Pareja M, Benito-Leon J et al. 1999. Serum levels of β-carotene, α-carotene and vitamin A in patients with Alzheimer's disease. Eur. J. Neurol. 6:495–97
    [Google Scholar]
  140. 140.  Foy CJ, Passmore AP, Vahidassr MD, Young IS, Lawson JT 1999. Plasma chain-breaking antioxidants in Alzheimer's disease, vascular dementia and Parkinson's disease. QJM 92:39–45
    [Google Scholar]
  141. 141.  Bourdel-Marchasson I, Delmas-Beauvieux MC, Peuchant E, Richard-Harston S, Decamps A et al. 2001. Antioxidant defences and oxidative stress markers in erythrocytes and plasma from normally nourished elderly Alzheimer patients. Age Ageing 30:235–41
    [Google Scholar]
  142. 142.  Mullan K, Williams MA, Cardwell CR, McGuinness B, Passmore P et al. 2017. Serum concentrations of vitamin E and carotenoids are altered in Alzheimer's disease: a case-control study. Alzheimers Dement 3:432–39
    [Google Scholar]
  143. 143.  Elstner M, Morris CM, Heim K, Bender A, Mehta D et al. 2011. Expression analysis of dopaminergic neurons in Parkinson's disease and aging links transcriptional dysregulation of energy metabolism to cell death. Acta Neuropathol 122:75–86
    [Google Scholar]
  144. 144.  Miller RM, Kiser GL, Kaysser-Kranich TM, Lockner RJ, Palaniappan C, Federoff HJ 2006. Robust dysregulation of gene expression in substantia nigra and striatum in Parkinson's disease. Neurobiol. Dis. 21:305–13
    [Google Scholar]
  145. 145.  Kim JH, Hwang J, Shim E, Chung EJ, Jang SH, Koh SB 2017. Association of serum carotenoid, retinol, and tocopherol concentrations with the progression of Parkinson's disease. Nutr. Res. Pract. 11:114–20
    [Google Scholar]
  146. 146.  Labadorf A, Hoss AG, Lagomarsino V, Latourelle JC, Hadzi TC et al. 2015. RNA sequence analysis of human Huntington disease brain reveals an extensive increase in inflammatory and developmental gene expression. PLOS ONE 10:e0143563
    [Google Scholar]
  147. 147.  Dangond F, Hwang D, Camelo S, Pasinelli P, Frosch MP et al. 2004. Molecular signature of late-stage human ALS revealed by expression profiling of postmortem spinal cord gray matter. Physiol. Genom. 16:229–39
    [Google Scholar]
  148. 148.  Iwasaki Y, Ikeda K, Kinoshita M 1995. Vitamin A and E levels are normal in amyotrophic lateral sclerosis. J. Neurol. Sci. 132:193–94
    [Google Scholar]
  149. 149.  Batra R, Hutt K, Vu A, Rabin SJ, Baughn MW et al. 2016. Gene expression signatures of sporadic ALS motor neuron populations. bioRxiv 038448. https://doi.org/10.1101/038448
    [Crossref]
  150. 150.  Testa G, Staurenghi E, Zerbinati C, Gargiulo S, Iuliano L et al. 2016. Changes in brain oxysterols at different stages of Alzheimer's disease: their involvement in neuroinflammation. Redox Biol 10:24–33
    [Google Scholar]
  151. 151.  Wisniewski T, Newman K, Javitt NB 2013. Alzheimer's disease: brain desmosterol levels. J. Alzheimers Dis. 33:881–88
    [Google Scholar]
  152. 152.  Bjorkhem I, Lovgren-Sandblom A, Leoni V, Meaney S, Brodin L et al. 2013. Oxysterols and Parkinson's disease: evidence that levels of 24S-hydroxycholesterol in cerebrospinal fluid correlates with the duration of the disease. Neurosci. Lett. 555:102–5
    [Google Scholar]
  153. 153.  Kreilaus F, Spiro AS, Hannan AJ, Garner B, Jenner AM 2015. Brain cholesterol synthesis and metabolism is progressively disturbed in the R6/1 mouse model of Huntington's disease: a targeted GC-MS/MS sterol analysis. J. Huntingtons Dis. 4:305–18
    [Google Scholar]
  154. 154.  Abdel-Khalik J, Yutuc E, Crick PJ, Gustafsson JA, Warner M et al. 2017. Defective cholesterol metabolism in amyotrophic lateral sclerosis. J. Lipid Res. 58:267–78
    [Google Scholar]
  155. 155.  Nasaruddin ML, Holscher C, Kehoe P, Graham SF, Green BD 2016. Wide-ranging alterations in the brain fatty acid complement of subjects with late Alzheimer's disease as detected by GC-MS. Am. J. Transl. Res. 8:154–65
    [Google Scholar]
  156. 156.  Abbott SK, Jenner AM, Spiro AS, Batterham M, Halliday GM, Garner B 2015. Fatty acid composition of the anterior cingulate cortex indicates a high susceptibility to lipid peroxidation in Parkinson's disease. J. Parkinsons Dis. 5:175–85
    [Google Scholar]
  157. 157.  Ilieva EV, Ayala V, Jove M, Dalfo E, Cacabelos D et al. 2007. Oxidative and endoplasmic reticulum stress interplay in sporadic amyotrophic lateral sclerosis. Brain 130:3111–23
    [Google Scholar]
  158. 158.  Lin L, Park JW, Ramachandran S, Zhang Y, Tseng YT et al. 2016. Transcriptome sequencing reveals aberrant alternative splicing in Huntington's disease. Hum. Mol. Genet. 25:3454–66
    [Google Scholar]
/content/journals/10.1146/annurev-pharmtox-010818-021807
Loading
/content/journals/10.1146/annurev-pharmtox-010818-021807
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error