Association of plasma and CSF cytochrome P450, soluble epoxide hydrolase, and ethanolamide metabolism with Alzheimer's disease.
Alzheimer’s disease
Cognition
Endocannabinoids
Lipid mediators
Oxylipins
Journal
Alzheimer's research & therapy
ISSN: 1758-9193
Titre abrégé: Alzheimers Res Ther
Pays: England
ID NLM: 101511643
Informations de publication
Date de publication:
06 09 2021
06 09 2021
Historique:
received:
10
03
2021
accepted:
25
08
2021
entrez:
7
9
2021
pubmed:
8
9
2021
medline:
14
9
2021
Statut:
epublish
Résumé
Alzheimer's disease, cardiovascular disease, and other cardiometabolic disorders may share inflammatory origins. Lipid mediators, including oxylipins, endocannabinoids, bile acids, and steroids, regulate inflammation, energy metabolism, and cell proliferation with well-established involvement in cardiometabolic diseases. However, their role in Alzheimer's disease is poorly understood. Here, we describe the analysis of plasma and cerebrospinal fluid lipid mediators in a case-control comparison of ~150 individuals with Alzheimer's disease and ~135 healthy controls, to investigate this knowledge gap. Lipid mediators were measured using targeted quantitative mass spectrometry. Data were analyzed using the analysis of covariates, adjusting for sex, age, and ethnicity. Partial least square discriminant analysis identified plasma and cerebrospinal fluid lipid mediator discriminates of Alzheimer's disease. Alzheimer's disease predictive models were constructed using machine learning combined with stepwise logistic regression. In both plasma and cerebrospinal fluid, individuals with Alzheimer's disease had elevated cytochrome P450/soluble epoxide hydrolase pathway components and decreased fatty acid ethanolamides compared to healthy controls. Circulating metabolites of soluble epoxide hydrolase and ethanolamides provide Alzheimer's disease predictors with areas under receiver operator characteristic curves ranging from 0.82 to 0.92 for cerebrospinal fluid and plasma metabolites, respectively. Previous studies report Alzheimer's disease-associated soluble epoxide hydrolase upregulation in the brain and that endocannabinoid metabolism provides an adaptive response to neuroinflammation. This study supports the involvement of P450-dependent and endocannabinoid metabolism in Alzheimer's disease. The results further suggest that combined pharmacological intervention targeting both metabolic pathways may have therapeutic benefits for Alzheimer's disease.
Sections du résumé
BACKGROUND
Alzheimer's disease, cardiovascular disease, and other cardiometabolic disorders may share inflammatory origins. Lipid mediators, including oxylipins, endocannabinoids, bile acids, and steroids, regulate inflammation, energy metabolism, and cell proliferation with well-established involvement in cardiometabolic diseases. However, their role in Alzheimer's disease is poorly understood. Here, we describe the analysis of plasma and cerebrospinal fluid lipid mediators in a case-control comparison of ~150 individuals with Alzheimer's disease and ~135 healthy controls, to investigate this knowledge gap.
METHODS
Lipid mediators were measured using targeted quantitative mass spectrometry. Data were analyzed using the analysis of covariates, adjusting for sex, age, and ethnicity. Partial least square discriminant analysis identified plasma and cerebrospinal fluid lipid mediator discriminates of Alzheimer's disease. Alzheimer's disease predictive models were constructed using machine learning combined with stepwise logistic regression.
RESULTS
In both plasma and cerebrospinal fluid, individuals with Alzheimer's disease had elevated cytochrome P450/soluble epoxide hydrolase pathway components and decreased fatty acid ethanolamides compared to healthy controls. Circulating metabolites of soluble epoxide hydrolase and ethanolamides provide Alzheimer's disease predictors with areas under receiver operator characteristic curves ranging from 0.82 to 0.92 for cerebrospinal fluid and plasma metabolites, respectively.
CONCLUSIONS
Previous studies report Alzheimer's disease-associated soluble epoxide hydrolase upregulation in the brain and that endocannabinoid metabolism provides an adaptive response to neuroinflammation. This study supports the involvement of P450-dependent and endocannabinoid metabolism in Alzheimer's disease. The results further suggest that combined pharmacological intervention targeting both metabolic pathways may have therapeutic benefits for Alzheimer's disease.
Identifiants
pubmed: 34488866
doi: 10.1186/s13195-021-00893-6
pii: 10.1186/s13195-021-00893-6
pmc: PMC8422756
doi:
Substances chimiques
Fatty Acids
0
Oxylipins
0
Cytochrome P-450 Enzyme System
9035-51-2
Epoxide Hydrolases
EC 3.3.2.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
149Subventions
Organisme : NIA NIH HHS
ID : R01 AG046171
Pays : United States
Organisme : NIA NIH HHS
ID : U19 AG063744
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG070937
Pays : United States
Organisme : NIH HHS
ID : U19AG063744
Pays : United States
Organisme : NIH HHS
ID : RF1AG051550
Pays : United States
Organisme : NIH HHS
ID : RF1AG058942
Pays : United States
Organisme : NIH HHS
ID : RF1AG057452
Pays : United States
Organisme : NIH HHS
ID : U01AG061359
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG066511
Pays : United States
Organisme : Foundation for the National Institutes of Health
ID : DAOU16AMPA
Organisme : NIA NIH HHS
ID : NIA R01AG046171
Pays : United States
Organisme : NIH HHS
ID : R01AG059093
Pays : United States
Informations de copyright
© 2021. The Author(s).
Références
Front Pharmacol. 2014 Mar 05;5:37
pubmed: 24634659
Elife. 2018 Nov 12;7:
pubmed: 30417826
Brain Res. 2020 Dec 15;1749:147135
pubmed: 32980333
Front Psychiatry. 2018 Dec 07;9:647
pubmed: 30581395
Life Sci. 2013 Mar 19;92(8-9):404-9
pubmed: 23178153
Arch Biochem Biophys. 2004 Jul 15;427(2):164-9
pubmed: 15196990
Acta Pharmacol Sin. 2018 Jul;39(7):1142-1154
pubmed: 29877318
Int J Mol Sci. 2020 Mar 26;21(7):
pubmed: 32224850
Nature. 2014 Jun 5;510(7503):92-101
pubmed: 24899309
Compr Physiol. 2013 Jul;3(3):1191-212
pubmed: 23897684
Cell Rep Med. 2020 Nov 17;1(8):100138
pubmed: 33294859
Prog Neurobiol. 2018 Jan;160:82-100
pubmed: 29097192
Arch Biochem Biophys. 2000 Apr 15;376(2):420-32
pubmed: 10775430
Metabolites. 2020 May 06;10(5):
pubmed: 32384774
J Lipid Res. 2017 Jan;58(1):188-195
pubmed: 27875258
Nat Rev Drug Discov. 2009 Oct;8(10):794-805
pubmed: 19794443
Prostaglandins Other Lipid Mediat. 2002 Aug;68-69:197-210
pubmed: 12432919
Br J Pharmacol. 2005 Feb;144(4):459-65
pubmed: 15655504
Alzheimers Dement. 2019 Jan;15(1):76-92
pubmed: 30337151
Nat Med. 1997 May;3(5):562-6
pubmed: 9142128
Hepatology. 2018 Feb;67(2):464-466
pubmed: 28926117
J Leukoc Biol. 2015 Jun;97(6):1049-70
pubmed: 25877930
Curr Pharm Des. 2008;14(23):2299-3305
pubmed: 18781980
Br J Pharmacol. 2017 Jun;174(11):1349-1365
pubmed: 27539936
Nat Genet. 2021 Feb;53(2):143-146
pubmed: 33510477
J Nutr Biochem. 2020 Dec;86:108484
pubmed: 32827665
Hum Mol Genet. 2006 May 15;15(10):1640-9
pubmed: 16595607
Best Pract Res Clin Gastroenterol. 2014 Aug;28(4):573-83
pubmed: 25194176
J Neurosci. 2007 Apr 25;27(17):4642-9
pubmed: 17460077
Front Cell Neurosci. 2014 Aug 01;8:195
pubmed: 25136293
J Cardiovasc Pharmacol. 2013 Sep;62(3):285-97
pubmed: 23676336
Pharmacol Ther. 2017 Dec;180:62-76
pubmed: 28642117
Adv Nutr. 2015 Sep 15;6(5):513-40
pubmed: 26374175
Int J Mol Sci. 2018 Mar 13;19(3):
pubmed: 29533978
Ann Neurol. 2009 Apr;65(4):403-13
pubmed: 19296504
Int J Mol Sci. 2020 Feb 22;21(4):
pubmed: 32098382
Methods Mol Biol. 2018;1730:175-212
pubmed: 29363074
PLoS One. 2010 Jun 04;5(6):e10956
pubmed: 20532041
Int J Mol Sci. 2020 Aug 20;21(17):
pubmed: 32825239
Sci Rep. 2020 May 15;10(1):8105
pubmed: 32415198
Front Aging Neurosci. 2016 Nov 22;8:263
pubmed: 27920719
JAMA Neurol. 2017 Oct 1;74(10):1178-1189
pubmed: 28846757
Anal Chim Acta. 2021 Jan 25;1143:189-200
pubmed: 33384117
Curr Neuropharmacol. 2012 Jun;10(2):159-66
pubmed: 23204985
Br J Pharmacol. 2012 Apr;165(8):2485-96
pubmed: 21506952
Biochimie. 2019 Apr;159:59-65
pubmed: 30716359
Neurosci Lett. 2015 Apr 23;593:56-60
pubmed: 25796175
Nihon Kyobu Shikkan Gakkai Zasshi. 1992 Mar;30(3):418-24
pubmed: 1569719
Neurotherapeutics. 2020 Oct;17(4):1825-1835
pubmed: 32488482
Nat Med. 2021 Jun;27(6):1034-1042
pubmed: 34031605
Int J Mol Sci. 2020 Aug 12;21(16):
pubmed: 32806612
J Neuroendocrinol. 2008 Jun;20(6):850-7
pubmed: 18601709
Sci Rep. 2019 Dec 13;9(1):19064
pubmed: 31836777
Aging Cell. 2020 Mar;19(3):e13113
pubmed: 32061032
Mol Pain. 2016 Jul 12;12:
pubmed: 27411353
Sci Rep. 2021 Sep 23;11(1):18964
pubmed: 34556796
Saudi J Biol Sci. 2015 Jan;22(1):19-23
pubmed: 25561878
J Med Chem. 2021 Feb 25;64(4):1856-1872
pubmed: 33550801
Front Physiol. 2016 Dec 26;7:646
pubmed: 28082913
J Neurochem. 2020 Jan;152(2):195-207
pubmed: 31283837
Neuroepidemiology. 2019;53(3-4):187-200
pubmed: 31454799
Prostaglandins. 1992 Mar;43(3):281-92
pubmed: 1631318
Sci Rep. 2019 Mar 13;9(1):4356
pubmed: 30867458
J Nutr Biochem. 2019 Jun;68:51-58
pubmed: 31030167
Pediatr Res. 2019 May;85(6):799-806
pubmed: 30420706
J Neural Transm (Vienna). 2009 Mar;116(3):301-5
pubmed: 19137236
J Mol Cell Cardiol. 2010 Feb;48(2):331-41
pubmed: 19891972
Am J Physiol Gastrointest Liver Physiol. 2017 Oct 1;313(4):G300-G312
pubmed: 28663304
Neurology. 1999 May 12;52(8):1555-62
pubmed: 10331678
Arterioscler Thromb Vasc Biol. 2016 Jul;36(7):1305-15
pubmed: 27174096
Cell Mol Neurobiol. 2018 Jan;38(1):121-132
pubmed: 28975471
J Alzheimers Dis. 2015;46(2):497-506
pubmed: 25818503
Prostaglandins Other Lipid Mediat. 2014 Oct;113-115:30-7
pubmed: 25277097
J Biol Chem. 2013 Jul 26;288(30):21618-29
pubmed: 23766516