Changes in brain oxysterols at different stages of Alzheimer's disease: Their involvement in neuroinflammation.
Alzheimer's disease (AD) is a gradually debilitating disease that leads to dementia. The molecular mechanisms underlying AD are still not clear, and at present no reliable biomarkers are available for the early diagnosis. In the last several years, together with oxidative stress and neuroinflammation, altered cholesterol metabolism in the brain has become increasingly implicated in AD progression. A significant body of evidence indicates that oxidized cholesterol, in the form of oxysterols, is one of the main triggers of AD. The oxysterols potentially most closely involved in the pathogenesis of AD are 24-hydroxycholesterol and 27-hydroxycholesterol, respectively deriving from cholesterol oxidation by the enzymes CYP46A1 and CYP27A1. However, the possible involvement of oxysterols resulting from cholesterol autooxidation, including 7-ketocholesterol and 7β-hydroxycholesterol, is now emerging. In a systematic analysis of oxysterols in post-mortem human AD brains, classified by the Braak staging system of neurofibrillary pathology, alongside the two oxysterols of enzymatic origin, a variety of oxysterols deriving from cholesterol autoxidation were identified; these included 7-ketocholesterol, 7α-hydroxycholesterol, 4β-hydroxycholesterol, 5α,6α-epoxycholesterol, and 5β,6β-epoxycholesterol. Their levels were quantified and compared across the disease stages. Some inflammatory mediators, and the proteolytic enzyme matrix metalloprotease-9, were also found to be enhanced in the brains, depending on disease progression. This highlights the pathogenic association between the trends of inflammatory molecules and oxysterol levels during the evolution of AD. Conversely, sirtuin 1, an enzyme that regulates several pathways involved in the anti-inflammatory response, was reduced markedly with the progression of AD, supporting the hypothesis that the loss of sirtuin 1 might play a key role in AD. Taken together, these results strongly support the association between changes in oxysterol levels and AD progression.
Department of Clinical and Biological Sciences, University of Turin, Orbassano, Turin, Italy.
Gabriella
G
Testa
Department of Clinical and Biological Sciences, University of Turin, Orbassano, Turin, Italy.
Erica
E
Staurenghi
Department of Medico-Surgical Sciences and Biotechnology, Vascular Biology and Mass Spectrometry Laboratory, Sapienza University of Rome, Latina, Italy.
Chiara
C
Zerbinati
Department of Clinical and Biological Sciences, University of Turin, Orbassano, Turin, Italy.
Simona
S
Gargiulo
Department of Medico-Surgical Sciences and Biotechnology, Vascular Biology and Mass Spectrometry Laboratory, Sapienza University of Rome, Latina, Italy.
Luigi
L
Iuliano
Foundation IRCCS Carlo Besta Institute of Neurology, Milan, Italy.
Giorgio
G
Giaccone
Geriatric Division, A.O.U. San Luigi Gonzaga, Orbassano, Turin, Italy.
Fausto
F
Fantò
Department of Clinical and Biological Sciences, University of Turin, Orbassano, Turin, Italy.
Giuseppe
G
Poli
Department of Clinical and Biological Sciences, University of Turin, Orbassano, Turin, Italy. Electronic address: gabriella.leonarduzzi@unito.it.
Gabriella
G
Leonarduzzi
Department of Clinical and Biological Sciences, University of Turin, Orbassano, Turin, Italy.
Paola
P
Gamba
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D053493:Cholestanetriol 26-Monooxygenase / Q000235:genetics; D000072556:Cholesterol 24-Hydroxylase / Q000235:genetics; D018450:Disease Progression; D005786:Gene Expression Regulation; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D018384:Oxidative Stress; D000072376:Oxysterols / Q000378:metabolism*; D056564:Sirtuin 1 / Q000235:genetics
D000072376:Oxysterols; D000072556:Cholesterol 24-Hydroxylase; C506831:CYP27A1 protein, human; D053493:Cholestanetriol 26-Monooxygenase; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C447939:SIRT1 protein, human; D056564:Sirtuin 1
Alzheimer's disease; Cholesterol metabolism; Inflammation; Oxysterols; Sirtuin-1
Free Radic Biol Med. 2013 Sep;62:157-69
23044265
Clin Sci (Lond). 2015 Dec;129(12):1195-206
26399707
Acta Neuropathol. 2006 Oct;112(4):389-404
16906426
N Engl J Med. 2010 Jan 28;362(4):329-44
20107219
Int J Dev Neurosci. 2006 Apr-May;24(2-3):157-65
16384684
J Chromatogr A. 2014 Oct 17;1364:214-22
25204266
Science. 2001 Aug 24;293(5534):1487-91
11520987
Mol Cell. 2007 Oct 12;28(1):91-106
17936707
J Biol Chem. 2001 Oct 19;276(42):38658-64
11509575
Acta Naturae. 2016 Jan-Mar;8(1):58-73
27099785
Neurodegener Dis. 2014;13(4):230-6
24022074
Int J Mol Sci. 2014 Dec 24;16(1):193-217
25547488
Neurosci Lett. 2002 Oct 18;331(3):171-4
12383924
J Lipid Res. 2003 Apr;44(4):793-9
12562838
J Neurochem. 2009 Sep;110(5):1445-56
19558452
Methods. 2001 Dec;25(4):402-8
11846609
Brain Res. 1999 Jun 5;830(2):226-36
10366679
Eur J Clin Invest. 2002 May;32(5):360-71
12027877
J Biol Chem. 2006 Aug 4;281(31):21745-54
16751189
Neuroscience. 2009 Feb 6;158(3):983-94
18621108
CNS Neurol Disord Drug Targets. 2016;15(3):329-36
26831258
Mol Aspects Med. 2009 Jun;30(3):171-9
19248803
Neurodegener Dis. 2010;7(1-3):38-41
20160456
Glia. 2001 Nov;36(2):165-79
11596125
J Neural Transm (Vienna). 2010 Aug;117(8):919-47
20632195
Lancet. 2001 Aug 11;358(9280):461-7
11513911
Lancet Neurol. 2011 Mar;10(3):275-9
21349442
J Neuropathol Exp Neurol. 2011 Nov;70(11):960-9
22002422
J Neuropathol Exp Neurol. 2011 Apr;70(4):292-301
21412171
J Neuropathol Exp Neurol. 2009 Jan;68(1):48-58
19104446
Acta Neuropathol. 1991;82(4):239-59
1759558
Neurosci Res. 2014 Feb;79:1-12
24144733
Neuroscience. 2003;121(2):307-14
14521990
PLoS One. 2013 Apr 16;8(4):e61560
23613875
Neuromolecular Med. 2014 Jun;16(2):405-14
24464653
EMBO J. 2004 Jun 16;23(12):2369-80
15152190
Acta Neuropathol. 2012 Jan;123(1):1-11
22101365
J Biol Chem. 2004 Aug 13;279(33):34674-81
15148325
J Neuropathol Exp Neurol. 2006 Jul;65(7):652-63
16825952
Steroids. 2015 Jul;99(Pt B):189-93
25668615
Acta Neuropathol. 2011 May;121(5):589-95
21516512
Pharmacol Res. 2013 Jun;72 :45-51
23542729
Alzheimers Dement. 2012 Jan;8(1):1-13
22265587
Biochem Pharmacol. 2014 Nov 1;92(1):142-8
25199460
Neuropathol Appl Neurobiol. 2009 Dec;35(6):532-54
19682326
Neuroscience. 2016 Mar 1;316:178-91
26724580
J Neurochem. 2009 Aug;110(4):1241-53
19522732
Cell Res. 2013 Jun;23(6):746-58
23689277
Mol Aspects Med. 2009 Jun;30(3):111-22
19248801
Ann Neurol. 2001 Jan;49(1):53-66
11198297
Neurosci Lett. 2001 Nov 13;314(1-2):45-8
11698143
Pharmacogenomics J. 2010 Oct;10(5):448-57
20038958
Front Aging Neurosci. 2015 Jun 19;7:119
26150787
Neuron. 2010 Sep 23;67(6):953-66
20869593
Brain Res Rev. 2008 Jun;58(1):96-105
18190968
Biochem Soc Trans. 2011 Aug;39(4):886-90
21787318
Clin Chem. 2015 Feb;61(2):400-11
25512642
PLoS One. 2014 May 06;9(5):e96795
24802026
Neurochem Res. 2012 Aug;37(8):1601-14
22461064
Science. 2001 Aug 24;293(5534):1491-5
11520988
J Biol Chem. 2005 Dec 2;280(48):40364-74
16183991
Exp Neurol. 2004 May;187(1):1-10
15081582
Clin Chim Acta. 2016 May 1;456:107-14
26944571
J Intern Med. 2006 Dec;260(6):493-508
17116000
Behav Neurol. 2016;2016:1501527
26880859
Biochem Soc Trans. 2014 Aug;42(4):1001-5
25109993
J Neurochem. 2010 Jan;112(1):34-41
19860851
Mol Neurobiol. 2009 Aug;40(1):15-32
19365736
Free Radic Biol Med. 2008 Jun 15;44(12):2051-7
18423383
Anal Biochem. 2003 Jan 15;312(2):217-23
12531208
Steroids. 2015 Jul;99(Pt B):172-7
25759118
Brain. 2015 Oct;138(Pt 10):2814-33
26283673
Neurosci Lett. 2010 May 26;476(1):36-41
20380872