Reduction of APOE accounts for neurobehavioral deficits in fetal alcohol spectrum disorders.

Publisher: Nature Publishing Group Specialist Journals Country of Publication: England NLM ID: 9607835 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5578 (Electronic) Linking ISSN: 13594184 NLM ISO Abbreviation: Mol Psychiatry Subsets: MEDLINE

Publication: 2000- : Houndmills, Basingstoke, UK : Nature Publishing Group Specialist Journals
Original Publication: Houndmills, Hampshire, UK ; New York, NY : Stockton Press, c1996-

Fetal Alcohol Spectrum Disorders*/metabolism ; Fetal Alcohol Spectrum Disorders*/genetics ; Apolipoproteins E*/genetics ; Apolipoproteins E*/metabolism ; Prenatal Exposure Delayed Effects*/metabolism ; Brain*/metabolism ; Genome-Wide Association Study*/methods; Animals ; Mice ; Female ; Humans ; Pregnancy ; Male ; Polymorphism, Single Nucleotide/genetics ; Disease Models, Animal ; Child ; Mice, Inbred C57BL ; Ethanol

A hallmark of fetal alcohol spectrum disorders (FASD) is neurobehavioral deficits that still do not have effective treatment. Here, we present that reduction of Apolipoprotein E (APOE) is critically involved in neurobehavioral deficits in FASD. We show that prenatal alcohol exposure (PAE) changes chromatin accessibility of Apoe locus, and causes reduction of APOE levels in both the brain and peripheral blood in postnatal mice. Of note, postnatal administration of an APOE receptor agonist (APOE-RA) mitigates motor learning deficits and anxiety in those mice. Several molecular and electrophysiological properties essential for learning, which are altered by PAE, are restored by APOE-RA. Our human genome-wide association study further reveals that the interaction of PAE and a single nucleotide polymorphism in the APOE enhancer which chromatin is closed by PAE in mice is associated with lower scores in the delayed matching-to-sample task in children. APOE in the plasma is also reduced in PAE children, and the reduced level is associated with their lower cognitive performance. These findings suggest that controlling the APOE level can serve as an effective treatment for neurobehavioral deficits in FASD.
(© 2024. The Author(s).)

Alcohol. 2015 Feb;49(1):79-87. (PMID: 25583378)
Prog Lipid Res. 2011 Jan;50(1):62-74. (PMID: 20854843)
J Pediatr. 2006 Jan;148(1):30-7. (PMID: 16423594)
J Clin Invest. 2015 May;125(5):2069-76. (PMID: 25866966)
Bioinformatics. 2015 Jan 15;31(2):166-9. (PMID: 25260700)
Neurotoxicol Teratol. 1995 Jul-Aug;17(4):437-43. (PMID: 7565490)
J Biochem. 2002 Nov;132(5):743-9. (PMID: 12417024)
J Neurosci. 2010 Dec 15;30(50):17068-78. (PMID: 21159977)
Biol Psychol. 2016 Oct;120:10-20. (PMID: 27481545)
Alcohol. 2010 Nov-Dec;44(7-8):635-41. (PMID: 20036488)
Bioinformatics. 2014 Apr 1;30(7):923-30. (PMID: 24227677)
Neuropsychol Rev. 2011 Jun;21(2):81-101. (PMID: 21503685)
Stem Cells Int. 2016;2016:2108495. (PMID: 26949399)
Front Pediatr. 2020 Jul 15;8:359. (PMID: 32760684)
Nat Rev Neurosci. 2013 Jun;14(6):383-400. (PMID: 23686171)
Int J Toxicol. 2004 Jan-Feb;23(1):47-54. (PMID: 15162847)
Nat Commun. 2020 Aug 31;11(1):4363. (PMID: 32868797)
J Clin Invest. 1985 Oct;76(4):1501-13. (PMID: 3932467)
J Biol Chem. 2011 Apr 22;286(16):13891-904. (PMID: 21372127)
Bioinformatics. 2012 Dec 15;28(24):3326-8. (PMID: 23060615)
J Lipid Res. 2017 Jun;58(6):1036-1043. (PMID: 28292942)
J Neurosci. 2002 Oct 15;22(20):8902-10. (PMID: 12388597)
eNeuro. 2018 Aug 2;5(4):. (PMID: 30079373)
Nat Neurosci. 1999 Apr;2(4):352-7. (PMID: 10204542)
Early Hum Dev. 2013 Jul;89(7):487-96. (PMID: 23597678)
J Clin Invest. 2020 May 1;130(5):2252-2269. (PMID: 32202514)
Neurobiol Dis. 2002 Mar;9(2):149-59. (PMID: 11895368)
Epigenetics Chromatin. 2015 Sep 28;8:39. (PMID: 26421061)
J Clin Sleep Med. 2012 Aug 15;8(4):421-9. (PMID: 22893773)
Alcohol Clin Exp Res. 1998 May;22(3):685-96. (PMID: 9622451)
Front Genet. 2018 Dec 04;9:610. (PMID: 30568673)
Nat Genet. 2016 Oct;48(10):1284-1287. (PMID: 27571263)
Mol Psychiatry. 2022 Aug;27(8):3468-3478. (PMID: 35484243)
Mol Neurodegener. 2013 Jul 17;8:25. (PMID: 23866919)
Neuron. 2002 Apr 11;34(2):235-44. (PMID: 11970865)
Bioinformatics. 2016 Jan 15;32(2):292-4. (PMID: 26428292)
Matern Child Health J. 2015 Dec;19(12):2605-14. (PMID: 26164422)
Nature. 2021 Nov;599(7883):102-107. (PMID: 34616039)
Gigascience. 2015 Feb 25;4:7. (PMID: 25722852)
Nat Biotechnol. 2019 Aug;37(8):907-915. (PMID: 31375807)
Brain Res. 1997 Mar 21;751(2):307-14. (PMID: 9099820)
J Neurophysiol. 1998 Feb;79(2):555-66. (PMID: 9463421)
Adv Pediatr Res. 2018;5(3):. (PMID: 33364429)
Nat Commun. 2017 Jun 09;8:15834. (PMID: 28598433)
Nat Neurosci. 2020 Apr;23(4):533-543. (PMID: 32203497)
Neurobiol Learn Mem. 2013 Oct;105:107-16. (PMID: 23623827)
Behav Brain Res. 2010 Dec 25;214(2):395-401. (PMID: 20600347)
Alcohol Clin Exp Res. 2001 Dec;25(12):1719-22. (PMID: 11781503)
Lancet Glob Health. 2017 Mar;5(3):e290-e299. (PMID: 28089487)
Nucleic Acids Res. 2015 Apr 20;43(7):e47. (PMID: 25605792)
Atherosclerosis. 2003 Jun;168(2):229-37. (PMID: 12801605)
J Biol Chem. 2013 Jul 26;288(30):21909-23. (PMID: 23760271)
J Alzheimers Dis. 2008 Apr;13(3):255-66. (PMID: 18430993)
Birth Defects Res A Clin Mol Teratol. 2014 Apr;100(4):277-83. (PMID: 24616297)
Glia. 2001 Mar 15;33(4):298-305. (PMID: 11246228)
Am J Med Genet. 1993 Nov 1;47(6):857-61. (PMID: 8279483)
Handb Exp Pharmacol. 2015;224:113-79. (PMID: 25522987)
J Biol Chem. 2008 May 2;283(18):12004-13. (PMID: 18321860)
JAMA. 2018 Feb 6;319(5):474-482. (PMID: 29411031)
Anim Reprod. 2022 Apr 22;19(1):e20210134. (PMID: 35493783)
J Neurosci. 2010 Mar 31;30(13):4590-600. (PMID: 20357110)
J Lab Clin Med. 2006 Mar;147(3):126-32. (PMID: 16503242)
Proc Natl Acad Sci U S A. 2023 Dec 12;120(50):e2304074120. (PMID: 38051767)
Mech Dev. 2000 Feb;90(2):181-93. (PMID: 10642437)
Am J Med Genet B Neuropsychiatr Genet. 2006 Apr 5;141B(3):261-8. (PMID: 16526044)
J Neurosci. 2013 Jan 16;33(3):1062-7. (PMID: 23325244)
Transl Psychiatry. 2022 Jan 20;12(1):24. (PMID: 35058425)
Ital J Pediatr. 2021 May 17;47(1):113. (PMID: 34001186)
PLoS One. 2009 Dec 07;4(12):e8191. (PMID: 19997607)
Nature. 2015 Apr 9;520(7546):180-5. (PMID: 25822789)
Sci Rep. 2020 Jun 17;10(1):9824. (PMID: 32555345)
Nat Neurosci. 2021 Jun;24(6):786-798. (PMID: 33958804)
Am J Physiol Regul Integr Comp Physiol. 2012 Nov 1;303(9):R903-8. (PMID: 22933021)
Alcohol Clin Exp Res. 2016 Jan;40(1):18-32. (PMID: 26727519)
Neuron. 1993 Oct;11(4):575-80. (PMID: 8398148)
J Neurosci. 2016 Sep 7;36(36):9490-504. (PMID: 27605622)
J Neurosci. 2016 Jan 20;36(3):685-700. (PMID: 26791201)
PLoS One. 2015 Mar 06;10(3):e0118721. (PMID: 25747876)
Nat Methods. 2012 Mar 04;9(4):357-9. (PMID: 22388286)
Neuron. 2016 Mar 16;89(6):1173-1179. (PMID: 26948893)
Bioinformatics. 2010 Sep 1;26(17):2190-1. (PMID: 20616382)
Bioinformatics. 2015 Jul 15;31(14):2382-3. (PMID: 25765347)
J Hum Genet. 2012 Jan;57(1):18-25. (PMID: 22089642)
Life Sci Alliance. 2023 Jun 8;6(8):. (PMID: 37290814)
Sci Rep. 2016 Nov 29;6:37968. (PMID: 27897242)
Am J Pathol. 1999 Feb;154(2):601-11. (PMID: 10027417)
Bioinformatics. 2013 Jan 1;29(1):15-21. (PMID: 23104886)
Neuron. 1996 Jan;16(1):89-101. (PMID: 8562094)
Nature. 2015 Oct 1;526(7571):68-74. (PMID: 26432245)
Mol Cell Biol. 2004 Oct;24(20):8872-83. (PMID: 15456862)
Sci Rep. 2019 Jun 27;9(1):9354. (PMID: 31249361)
Mol Neurodegener. 2016 Dec 8;11(1):74. (PMID: 27931262)
J Physiol. 1996 Dec 1;497 ( Pt 2):437-55. (PMID: 8961186)
Nucleic Acids Res. 2014 Jul;42(Web Server issue):W187-91. (PMID: 24799436)
Alcohol Clin Exp Res. 2019 Jun;43(6):1046-1062. (PMID: 30964197)
Int J Mol Sci. 2018 Nov 23;19(12):. (PMID: 30477115)
Front Synaptic Neurosci. 2019 Oct 31;11:18. (PMID: 31736736)
Learn Mem. 2020 Oct 15;27(11):467-476. (PMID: 33060284)
Nat Commun. 2013;4:2258. (PMID: 23978820)
Exp Neurol. 1995 Dec;136(2):107-22. (PMID: 7498401)
Mol Neurodegener. 2013 May 17;8:16. (PMID: 23684315)
Alcohol Clin Exp Res (Hoboken). 2023 Feb;47(2):263-272. (PMID: 36807293)
J Neurosci. 2016 Sep 28;36(39):10141-50. (PMID: 27683909)
Bioinformatics. 2010 Sep 15;26(18):2336-7. (PMID: 20634204)
Nat Methods. 2017 Oct;14(10):959-962. (PMID: 28846090)
J Alzheimers Dis. 2013;36(2):335-47. (PMID: 23603398)
J Biol Chem. 2011 Feb 4;286(5):3839-50. (PMID: 21115487)
Nature. 2009 Dec 17;462(7275):920-4. (PMID: 19946265)
Bioinformatics. 2009 Aug 15;25(16):2078-9. (PMID: 19505943)
Behav Brain Res. 2006 Jul 15;171(1):116-26. (PMID: 16677723)
J Neurosci. 2003 Jun 15;23(12):5208-18. (PMID: 12832545)
J Biol Chem. 2002 Aug 30;277(35):31900-8. (PMID: 12032151)
Ann N Y Acad Sci. 2008 Nov;1144:154-75. (PMID: 19076375)
Biochemistry. 2004 Jun 15;43(23):7328-35. (PMID: 15182176)
Bioinformatics. 2010 Mar 15;26(6):841-2. (PMID: 20110278)
Epigenetics Chromatin. 2016 Jun 29;9:25. (PMID: 27358653)
JCI Insight. 2021 May 10;6(9):. (PMID: 33822768)
J Biol Chem. 2000 Oct 13;275(41):31567-72. (PMID: 10893248)
Alcohol Clin Exp Res. 2014 Dec;38(12):2962-8. (PMID: 25581651)
J Pharmacol Exp Ther. 2010 Jul;334(1):106-15. (PMID: 20406857)
J Neurosci. 2001 Feb 1;21(3):812-22. (PMID: 11157067)
Trends Endocrinol Metab. 2017 Apr;28(4):273-284. (PMID: 28057414)
Behav Brain Res. 2013 Apr 15;243:79-90. (PMID: 23295389)

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0 (Apolipoproteins E)
3K9958V90M (Ethanol)

Date Created: 20240511 Date Completed: 20241107 Latest Revision: 20241109

20241112

PMC11541007

10.1038/s41380-024-02586-6

38734844