title: Cigarette Smoke-Induced Alterations in Frontal White Matter Lipid Profiles Demonstrated by MALDI-Imaging Mass Spectrometry: Relevance to Alzheimer's Disease.
abstract: BACKGROUND
  Meta-analysis has shown that smokers have significantly increased risks for Alzheimer's disease (AD), and neuroimaging studies showed that smoking alters white matter (WM) structural integrity.
  
  
  OBJECTIVE
  Herein, we characterize the effects of cigarette smoke (CS) exposures and withdrawal on WM myelin lipid composition using matrix assisted laser desorption and ionization-imaging mass spectrometry (MALDI-IMS).
  
  
  METHODS
  Young adult male A/J mice were exposed to air (8 weeks; A8), CS (4 or 8 weeks; CS4, CS8), or CS8 followed by 2 weeks recovery (CS8 + R). Frontal lobe WM was examined for indices of lipid and protein oxidation and lipid profile alterations by MALDI-IMS. Lipid ions were identified by MS/MS with the LIPID MAPS prediction tools database. Inter-group comparisons were made using principal component analysis and R-generated heatmap.
  
  
  RESULTS
  CS increased lipid and protein adducts such that higher levels were present in CS8 compared with CS4 samples. CS8 + R reversed CS8 effects and normalized the levels of oxidative stress. MALDI-IMS demonstrated striking CS-associated alterations in WM lipid profiles characterized by either reductions or increases in phospholipids (phosphatidylinositol, phosphatidylserine, phosphatidylcholine, or phosphatidylethanolamine) and sphingolipids (sulfatides), and partial reversal of CS's inhibitory effects with recovery. The heatmap hierarchical dendrogram and PCA distinguished CS exposure, duration, and withdrawal effects on WM lipid profiles.
  
  
  CONCLUSIONS
  CS-mediated WM degeneration is associated with lipid peroxidation, protein oxidative injury, and alterations in myelin lipid composition, including shifts in phospholipids and sphingolipids needed for membrane integrity, plasticity, and intracellular signaling. Future goals are to delineate WM abnormalities in AD using MALDI-IMS, and couple the findings with MRI-mass spectroscopy to improve in vivo diagnostics and early detection of brain biochemical responses to treatment.
authors.affiliation: Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.|Molecular Pharmacology, Physiology, and Biotechnology, Providence, RI, USA.
authors.forename: Kavin
authors.initials: K
authors.lastname: Nunez
authors.affiliation: Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.|Departments of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: Jared
authors.initials: J
authors.lastname: Kay
authors.affiliation: Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.|Pathobiology Graduate Programs at Brown University, Providence, RI, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Krotow
authors.affiliation: Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.|Departments of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Tong
authors.affiliation: The Department of Pharmacology Pharmaceutical Sciences School of Pharmacy, University of Southern California, Los Angeles, CA, USA.
authors.forename: Amit R
authors.initials: AR
authors.lastname: Agarwal
authors.affiliation: The Department of Pharmacology Pharmaceutical Sciences School of Pharmacy, University of Southern California, Los Angeles, CA, USA.
authors.forename: Enrique
authors.initials: E
authors.lastname: Cadenas
authors.affiliation: Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.|Divisions of Gastroenterology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.|Divisions of Neuropathology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.|Departments of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.|Departments of Pathology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.|Departments of Neurology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.|Departments of Neurosurgery, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: de la Monte
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D015237:Dinoprost / Q000031:analogs & derivatives / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005625:Frontal Lobe / Q000473:pathology*; D050356:Lipid Metabolism / Q000187:drug effects*; D008297:Male; D051379:Mice; D010743:Phospholipids / Q000378:metabolism*; D025341:Principal Component Analysis; D050050:Protein Carbonylation; D012907:Smoking / Q000473:pathology*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism / Q000473:pathology; D066127:White Matter / Q000473:pathology*
chemical_list: D000447:Aldehydes; D010743:Phospholipids; C462359:tert-4-hydroxy-2-nonenal; C075750:8-epi-prostaglandin F2alpha; D015237:Dinoprost
keywords: Alzheimer’s disease; MALDI; cigarette smoke; imaging mass spectrometry; mouse model; neurodegeneration; tobacco; white matter
references.citation: J Alzheimers Dis. 2012;30 Suppl 2:S217-29
references.pmid: 22297646
references.citation: J Alzheimers Dis. 2009;16(4):705-14
references.pmid: 19387107
references.citation: J Biol Chem. 1994 Feb 11;269(6):4317-26
references.pmid: 8307999
references.citation: Biol Psychiatry. 2004 Jan 1;55(1):77-84
references.pmid: 14706428
references.citation: J Alzheimers Dis. 2009;17(4):827-44
references.pmid: 20387270
references.citation: Drug Alcohol Depend. 2012 Apr 1;122(1-2):105-11
references.pmid: 21992872
references.citation: J Biol Chem. 2007 Jan 5;282(1):329-36
references.pmid: 17107953
references.citation: Mol Neurobiol. 2008 Apr-Jun;37(2-3):93-103
references.pmid: 18465098
references.citation: Neuropathol Appl Neurobiol. 2003 Apr;29(2):159-69
references.pmid: 12662323
references.citation: Histopathology. 1990 May;16(5):433-9
references.pmid: 2361659
references.citation: Eur J Neurosci. 2006 Sep;24(6):1744-50
references.pmid: 17004938
references.citation: Cancer Epidemiol Biomarkers Prev. 2008 Apr;17(4):945-8
references.pmid: 18398035
references.citation: ACS Comb Sci. 2012 Jun 11;14(6):347-51
references.pmid: 22587990
references.citation: J Alzheimers Dis. 2009;17 (4):817-25
references.pmid: 19542621
references.citation: PLoS One. 2014 Mar 24;9(3):e92498
references.pmid: 24663285
references.citation: J Occup Environ Med. 2011 Oct;53(10 ):1128-33
references.pmid: 21915069
references.citation: Neurobiol Aging. 2010 Mar;31(3):398-408
references.pmid: 18547682
references.citation: Alcohol Alcohol. 2015 Nov;50(6):670-9
references.pmid: 26373814
references.citation: Alcohol Clin Exp Res. 2005 Aug;29(8):1484-95
references.pmid: 16131857
references.citation: Ann Neurol. 2003 Jul;54(1):7-8
references.pmid: 12838515
references.citation: J Hepatol. 2014 May;60(5):1063-74
references.pmid: 24412608
references.citation: J Alzheimers Dis. 2015 ;50(2):373-86
references.pmid: 26682684
references.citation: Alcohol Alcohol. 2015 Nov;50(6):680-9
references.pmid: 26373813
references.citation: J Alzheimers Dis. 2015 ;50(1):133-48
references.pmid: 26639972
references.citation: J Proteomics. 2011 Nov 18;74(12 ):2691-702
references.pmid: 21609791
references.citation: Int J Geriatr Psychiatry. 2005 Oct;20(10):919-26
references.pmid: 16163742
references.citation: J Am Soc Mass Spectrom. 2007 Jan;18(1):17-26
references.pmid: 17005416
references.citation: Mol Neurobiol. 2014 Aug;50(1):239-45
references.pmid: 24705861
references.citation: Neurosci Res. 2004 Jan;48(1):93-100
references.pmid: 14687885
references.citation: Cancer Epidemiol Biomarkers Prev. 2006 Dec;15(12 ):2378-83
references.pmid: 17164359
references.citation: J Alzheimers Dis. 2005 Dec;8(3):247-68
references.pmid: 16340083
references.citation: Neuroscience. 2014 Sep 12;276:206-15
references.pmid: 24583036
references.citation: J Alzheimers Dis. 2012;30 Suppl 2:S231-49
references.pmid: 22337830
references.citation: Alcohol. 2007 Nov;41(7):489-501
references.pmid: 17923369
references.citation: Addict Biol. 2012 Jul;17(4):817-25
references.pmid: 21392170
references.citation: Mol Neurodegener. 2009 Dec 24;4:54
references.pmid: 20034403
references.citation: Ann Neurol. 1986 Mar;19(3):253-62
references.pmid: 3963770
references.citation: Am J Geriatr Psychiatry. 2008 Jan;16(1):92-8
references.pmid: 18165464
references.citation: J Clin Invest. 1992 Dec;90(6):2502-7
references.pmid: 1469101
references.citation: Neuropsychopharmacology. 2014 Oct;39(11):2594-600
references.pmid: 24832823
references.citation: Addict Biol. 2012 Nov;17(6):977-80
references.pmid: 20731627
references.citation: Toxicol In Vitro. 2014 Sep;28(6):1097-105
references.pmid: 24835565
references.citation: J Alzheimers Dis. 2004 Dec;6(6 Suppl):S53-9
references.pmid: 15665415
references.citation: Am J Physiol Lung Cell Mol Physiol. 2012 Nov 15;303(10):L889-98
references.pmid: 23064950
references.citation: Biochem J. 2005 Nov 1;391(Pt 3):465-72
references.pmid: 15943586
references.citation: Biochim Biophys Acta. 1994 Mar 3;1211(2):125-49
references.pmid: 8117740
references.citation: Alzheimer Dis Assoc Disord. 1987;1(3):156-70
references.pmid: 3453747
references.citation: Alzheimers Dement. 2012 Nov;8(6):513-9
references.pmid: 23102121
references.citation: Annu Rev Physiol. 1998;60:643-65
references.pmid: 9558480
references.citation: Sci STKE. 2005 Jan 25;2005(268):pe3
references.pmid: 15671480
references.citation: J Histochem Cytochem. 2015 Oct;63(10 ):762-71
references.pmid: 26209083
references.citation: Curr Alzheimer Res. 2007 Apr;4(2):147-52
references.pmid: 17430239
references.citation: J Gastroenterol Hepatol. 2012 Mar;27 Suppl 2:33-41
references.pmid: 22320914
references.citation: J Neurochem. 2002 Aug;82(4):809-18
references.pmid: 12358786
references.citation: Liver. 1994 Dec;14(6):281-7
references.pmid: 7533231
references.citation: Prostaglandins Leukot Essent Fatty Acids. 2000 Sep;63(3):149-52
references.pmid: 10991772
references.citation: Clin Sci (Lond). 2004 Mar;106(3):261-8
references.pmid: 14556645
references.citation: Proc Natl Acad Sci U S A. 1996 Nov 12;93(23):13280-5
references.pmid: 8917582
references.citation: BMB Rep. 2008 Aug 31;41(8):560-7
references.pmid: 18755070
references.citation: Neuromolecular Med. 2010 Dec;12(4):331-40
references.pmid: 20571935
references.citation: Cancer Epidemiol Biomarkers Prev. 2005 Apr;14(4):885-91
references.pmid: 15824160
references.citation: Neurol Sci. 2013 Jun;34(6):813-7
references.pmid: 23207549
references.citation: J Lipid Res. 2012 Aug;53(8):1437-50
references.pmid: 22619219
references.citation: Methods. 2010 Apr;50(4):323-35
references.pmid: 20079843
references.citation: Int J Environ Res Public Health. 2009 Jul;6(7):2055-75
references.pmid: 19742171
references.citation: Carcinogenesis. 1991 Feb;12(2):257-61
references.pmid: 1995191
references.citation: NMR Biomed. 2009 Jun;22(5):516-22
references.pmid: 19156697
references.citation: Am J Respir Cell Mol Biol. 2014 Aug;51(2):284-93
references.pmid: 24625219
references.citation: Mov Disord. 2013 Apr;28(4):425-38
references.pmid: 23450518
references.citation: Alcohol Clin Exp Res. 2015 Dec;39(12 ):2324-33
references.pmid: 26756797
references.citation: Ann Neurol. 1989 May;25(5):450-9
references.pmid: 2774485
references.citation: Arch Med Res. 2012 Nov;43(8):671-6
references.pmid: 23142262
references.citation: Alzheimers Dement. 2014 Jun;10(3 Suppl):S122-45
references.pmid: 24924665
references.citation: Anal Chem. 2012 Feb 7;84(3):1557-64
references.pmid: 22243218
references.citation: Alzheimer Dis Assoc Disord. 2006 Oct-Dec;20(4):298-301
references.pmid: 17132977
references.citation: Neurobiol Aging. 2004 Aug;25(7):843-51
references.pmid: 15212838
references.citation: Exp Cell Res. 2007 Jun 10;313(10 ):2033-49
references.pmid: 17531973
references.citation: Neuromolecular Med. 2010 Dec;12(4):301-5
references.pmid: 20737248
references.citation: J Biol Chem. 2005 Jul 29;280(30):28110-7
references.pmid: 15923191
references.citation: Nicotine Tob Res. 2008 Jan;10(1):137-47
references.pmid: 18188754
references.citation: Brain. 1988 Dec;111 ( Pt 6):1425-39
references.pmid: 3208064
references.citation: J Alzheimers Dis. 2010;21(3):967-84
references.pmid: 20693650
references.citation: Neurol Res. 2004 Jul;26(5):488-95
references.pmid: 15265265
references.citation: Alcohol Alcohol. 2015 Mar;50(2):118-31
references.pmid: 25618784
references.citation: J Alzheimers Dis. 2010;19(2):465-80
references.pmid: 20110594
references.citation: Biochim Biophys Acta. 2010 Aug;1801(8):878-86
references.pmid: 20452460