title: Amyloid β inhibits retinoic acid synthesis exacerbating Alzheimer disease pathology which can be attenuated by an retinoic acid receptor α agonist.
abstract: The retinoic acid receptor (RAR) α system plays a key role in the adult brain, participating in the homeostatic control of synaptic plasticity, essential for memory function. Here we show that RARα signalling is down-regulated by amyloid beta (Aβ), which inhibits the synthesis of the endogenous ligand, retinoic acid (RA). This results in the counteraction of a variety of RARα-activated pathways that are key in the aetiopathology of Alzheimer's disease (AD) but which can be reversed by an RARα agonist. RARα signalling improves cognition in the Tg2576 mice, it has an anti-inflammatory effect and promotes Aβ clearance by increasing insulin degrading enzyme and neprilysin activity in both microglia and neurons. In addition, RARα signalling prevents tau phosphorylation. Therefore, stimulation of the RARα signalling pathway using a synthetic agonist, by both clearing Aβ and counteracting some of its toxic effects, offers therapeutic potential for the treatment of AD.
authors: The Wolfson Centre For Age-Related Diseases, King's College London, Guy's Campus, London, SE11UL, UK.
authors: Maria B
authors: MB
authors: Goncalves
authors: Earl
authors: E
authors: Clarke
authors: Carl
authors: C
authors: Hobbs
authors: Tony
authors: T
authors: Malmqvist
authors: Robert
authors: R
authors: Deacon
authors: Julian
authors: J
authors: Jack
authors: Jonathan P T
authors: JP
authors: Corcoran
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D003071:Cognition / Q000187:drug effects; D015536:Down-Regulation; D007339:Insulysin / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000378:metabolism; D015260:Neprilysin / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D047490:Retinoid X Receptor alpha / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014212:Tretinoin / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D001565:Benzoates; D047490:Retinoid X Receptor alpha; D013764:Tetrahydronaphthalenes; C068073:Am 580; D014212:Tretinoin; D015260:Neprilysin; D007339:Insulysin
references: Brain Res. 2012 Mar 20;1444:87-95
references: 22325097
references: Neurobiol Aging. 2006 Nov;27(11):1673-83
references: 16271805
references: Int Rev Neurobiol. 2007;82:235-46
references: 17678964
references: Cell. 2010 Jul 23;142(2):320-32
references: 20655472
references: Neuron. 1993 Feb;10(2):243-54
references: 8094963
references: J Neurochem. 2012 Jan;120 Suppl 1:167-185
references: 22122230
references: Dev Biol. 1999 Sep 15;213(2):390-404
references: 10479456
references: Dev Biol. 2005 Feb 1;278(1):60-70
references: 15649461
references: J Neurosci. 2008 Nov 5;28(45):11622-34
references: 18987198
references: J Mol Neurosci. 2004;22(1-2):5-11
references: 14742905
references: J Neurochem. 2012 Jan;120 Suppl 1:125-139
references: 22121920
references: J Neurochem. 2012 Jan;120 Suppl 1:186-193
references: 21883222
references: Neuron. 2005 Dec 22;48(6):913-22
references: 16364896
references: Neurobiol Dis. 2010 Mar;37(3):503-9
references: 19833208
references: J Biol Chem. 2010 Nov 26;285(48):37405-14
references: 20876579
references: Eur J Neurosci. 2010 Oct;32(8):1246-55
references: 20950278
references: Cold Spring Harb Perspect Med. 2011 Sep;1(1):a006189
references: 22229116
references: Nutr Rev. 2006 Dec;64(12):532-8
references: 17274495
references: Nat Rev Neurosci. 2007 Oct;8(10):755-65
references: 17882253
references: J Biol Chem. 2008 Jul 25;283(30):20841-7
references: 18495661
references: Nat Rev Neurosci. 2007 Jul;8(7):499-509
references: 17551515
references: Gene. 2011 Nov 15;488(1-2):1-12
references: 21699964
references: Proc Natl Acad Sci U S A. 2008 Oct 14;105(41):16015-20
references: 18840692
references: Biofactors. 2011 May-Jun;37(3):189-96
references: 21698698
references: Neurobiol Dis. 2010 Jan;37(1):147-55
references: 19800972
references: Nat Neurosci. 2009 Feb;12(2):119-21
references: 19122666
references: Nat Neurosci. 2009 Dec;12(12):1567-76
references: 19935655
references: Am J Pathol. 2011 Oct;179(4):2071-82
references: 21854751
references: Biochim Biophys Acta. 2011 Aug;1812(8):1023-31
references: 20970498
references: Science. 2002 Jul 19;297(5580):353-6
references: 12130773
references: Lancet. 1997 Oct 18;350(9085):1176
references: 9343525
references: J Biol Chem. 1997 Mar 7;272(10):6641-6
references: 9045694
references: Int J Biochem Cell Biol. 2005 Feb;37(2):289-305
references: 15474976
references: Neuroscience. 2011 Feb 3;174:132-42
references: 21130848
references: J Neurochem. 2002 Apr;81(1):1-8
references: 12067222
references: Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2901-5
references: 12604774
references: J Neurosci. 2008 Aug 13;28(33):8354-60
references: 18701698
references: Eur J Neurosci. 2004 Aug;20(4):896-902
references: 15305858
references: J Cell Biol. 1980 Jun;85(3):890-902
references: 6248568
references: Biochim Biophys Acta. 2011 May;1813(5):965-73
references: 20950656
references: J Neurosci. 2003 Jul 2;23(13):5531-5
references: 12843253
references: Science. 2012 Mar 23;335(6075):1503-6
references: 22323736
references: J Neurosci. 2000 Mar 1;20(5):1657-65
references: 10684867
references: Nat Protoc. 2006;1(3):1117-9
references: 17406392
references: Glia. 2002 Nov;40(2):260-9
references: 12379913
references: Ann Neurol. 2011 May;69(5):819-30
references: 21472769
references: J Neurosci Methods. 2010 Jul 15;190(2):171-9
references: 20452375
references: Nat Protoc. 2006;1(1):7-12
references: 17406205
references: Proc Natl Acad Sci U S A. 2011 Apr 5;108(14):5819-24
references: 21421841
references: J Biol Chem. 2011 May 27;286(21):18414-25
references: 21460223
references: Neuron. 2008 Jun 12;58(5):681-93
references: 18549781
references: FASEB J. 2009 Jun;23(6):1643-54
references: 19144697
references: Science. 2010 Dec 24;330(6012):1774
references: 21148344
references: Neuron. 2003 Dec 18;40(6):1087-93
references: 14687544
references: Brain Res Bull. 2012 Jan 4;87(1):10-20
references: 22024597
references: J Biol Chem. 2009 Jul 31;284(31):20909-16
references: 19491104
references: Prog Neurobiol. 2005 Mar;75(4):275-93
references: 15882777
references: Neuron. 2008 Oct 23;60(2):308-20
references: 18957222
references: J Neurosci. 2011 Dec 7;31(49):17764-71
references: 22159093
references: Dev Psychol. 2009 Jan;45(1):139-50
references: 19209997
references: J Neurosci. 2008 Dec 31;28(53):14537-45
references: 19118188
references: Front Mol Neurosci. 2012 Feb 15;5:16
references: 22419906