Domino-like effect of C112R mutation on ApoE4 aggregation and its reduction by Alzheimer's Disease drug candidate.
3-sulfopropanoic acid
Aggregation
Alzheimer’s disease
Apolipoprotein E
Cerebral organoids
HDX-MS
Lipidomics
Molecular dynamics
Neurodegeneration
Protein crystallography
Proteomics
Tramiprosate
Journal
Molecular neurodegeneration
ISSN: 1750-1326
Titre abrégé: Mol Neurodegener
Pays: England
ID NLM: 101266600
Informations de publication
Date de publication:
06 06 2023
06 06 2023
Historique:
received:
06
11
2022
accepted:
19
04
2023
medline:
8
6
2023
pubmed:
7
6
2023
entrez:
6
6
2023
Statut:
epublish
Résumé
Apolipoprotein E (ApoE) ε4 genotype is the most prevalent risk factor for late-onset Alzheimer's Disease (AD). Although ApoE4 differs from its non-pathological ApoE3 isoform only by the C112R mutation, the molecular mechanism of its proteinopathy is unknown. Here, we reveal the molecular mechanism of ApoE4 aggregation using a combination of experimental and computational techniques, including X-ray crystallography, site-directed mutagenesis, hydrogen-deuterium mass spectrometry (HDX-MS), static light scattering and molecular dynamics simulations. Treatment of ApoE ε3/ε3 and ε4/ε4 cerebral organoids with tramiprosate was used to compare the effect of tramiprosate on ApoE4 aggregation at the cellular level. We found that C112R substitution in ApoE4 induces long-distance (> 15 Å) conformational changes leading to the formation of a V-shaped dimeric unit that is geometrically different and more aggregation-prone than the ApoE3 structure. AD drug candidate tramiprosate and its metabolite 3-sulfopropanoic acid induce ApoE3-like conformational behavior in ApoE4 and reduce its aggregation propensity. Analysis of ApoE ε4/ε4 cerebral organoids treated with tramiprosate revealed its effect on cholesteryl esters, the storage products of excess cholesterol. Our results connect the ApoE4 structure with its aggregation propensity, providing a new druggable target for neurodegeneration and ageing.
Sections du résumé
BACKGROUND
Apolipoprotein E (ApoE) ε4 genotype is the most prevalent risk factor for late-onset Alzheimer's Disease (AD). Although ApoE4 differs from its non-pathological ApoE3 isoform only by the C112R mutation, the molecular mechanism of its proteinopathy is unknown.
METHODS
Here, we reveal the molecular mechanism of ApoE4 aggregation using a combination of experimental and computational techniques, including X-ray crystallography, site-directed mutagenesis, hydrogen-deuterium mass spectrometry (HDX-MS), static light scattering and molecular dynamics simulations. Treatment of ApoE ε3/ε3 and ε4/ε4 cerebral organoids with tramiprosate was used to compare the effect of tramiprosate on ApoE4 aggregation at the cellular level.
RESULTS
We found that C112R substitution in ApoE4 induces long-distance (> 15 Å) conformational changes leading to the formation of a V-shaped dimeric unit that is geometrically different and more aggregation-prone than the ApoE3 structure. AD drug candidate tramiprosate and its metabolite 3-sulfopropanoic acid induce ApoE3-like conformational behavior in ApoE4 and reduce its aggregation propensity. Analysis of ApoE ε4/ε4 cerebral organoids treated with tramiprosate revealed its effect on cholesteryl esters, the storage products of excess cholesterol.
CONCLUSIONS
Our results connect the ApoE4 structure with its aggregation propensity, providing a new druggable target for neurodegeneration and ageing.
Identifiants
pubmed: 37280636
doi: 10.1186/s13024-023-00620-9
pii: 10.1186/s13024-023-00620-9
pmc: PMC10245438
doi:
Substances chimiques
Apolipoprotein E4
0
Apolipoprotein E3
0
tramiprosate
5K8EAX0G53
Apolipoproteins E
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
38Informations de copyright
© 2023. The Author(s).
Références
J Biomed Sci. 2020 Jan 6;27(1):18
pubmed: 31906949
Protein Eng. 1994 Mar;7(3):385-91
pubmed: 8177887
Biophys J. 2000 Mar;78(3):1606-19
pubmed: 10692345
Methods. 2011 Sep;55(1):94-106
pubmed: 21821126
J Comput Chem. 1999 Jun;20(8):786-798
pubmed: 35619462
Neuron. 2018 Jun 27;98(6):1141-1154.e7
pubmed: 29861287
Diabetol Metab Syndr. 2013 May 14;5(1):24
pubmed: 23672807
J Neurosci. 2012 Sep 19;32(38):13125-36
pubmed: 22993429
Anal Chem. 2023 Feb 14;95(6):3160-3167
pubmed: 36724094
J Med Chem. 2019 Apr 25;62(8):4120-4130
pubmed: 30933499
Nat Commun. 2022 Aug 11;13(1):4726
pubmed: 35953482
Proc Natl Acad Sci U S A. 2013 May 7;110(19):E1807-16
pubmed: 23620513
Biophys J. 2017 Dec 19;113(12):2682-2694
pubmed: 29262361
Stem Cell Res. 2019 Oct;40:101563
pubmed: 31494448
J Chem Theory Comput. 2015 Apr 14;11(4):1864-74
pubmed: 26574392
Transl Psychiatry. 2019 Apr 26;9(1):144
pubmed: 31028243
Mol Neurobiol. 2019 Apr;56(4):2450-2465
pubmed: 30032423
Nat Neurosci. 2022 Aug;25(8):1020-1033
pubmed: 35915180
J Exp Med. 2012 Nov 19;209(12):2149-56
pubmed: 23129750
Biochemistry. 2011 Nov 1;50(43):9273-82
pubmed: 21899263
Transl Psychiatry. 2015 Jan 13;5:e494
pubmed: 25585166
J Neurosci. 2019 Sep 11;39(37):7408-7427
pubmed: 31331998
FEBS Lett. 2019 Jun;593(11):1144-1153
pubmed: 31058310
Anal Chem. 2018 Jun 19;90(12):7608-7616
pubmed: 29807422
J Mol Biol. 2019 May 31;431(12):2248-2265
pubmed: 31051176
J Chem Theory Comput. 2009 Sep 8;5(9):2371-7
pubmed: 26616618
EMBO Mol Med. 2012 Aug;4(8):730-42
pubmed: 22628224
Protein Sci. 2007 Jul;16(7):1389-97
pubmed: 17586772
Cell Stem Cell. 2019 Mar 7;24(3):363-375.e9
pubmed: 30686764
Proc Natl Acad Sci U S A. 2011 Sep 6;108(36):14813-8
pubmed: 21873229
Int J Mol Sci. 2020 Sep 01;21(17):
pubmed: 32882843
Nat Rev Neurol. 2019 Sep;15(9):501-518
pubmed: 31367008
Science. 1993 Aug 13;261(5123):921-3
pubmed: 8346443
J Lipid Res. 2009 Apr;50 Suppl:S183-8
pubmed: 19106071
J Biol Chem. 1981 Sep 10;256(17):9077-83
pubmed: 7263700
Front Aging Neurosci. 2018 Nov 02;10:285
pubmed: 30455639
Protein Sci. 2015 Jan;24(1):138-44
pubmed: 25377861
Neurobiol Aging. 2007 Apr;28(4):537-47
pubmed: 16675063
Proc Natl Acad Sci U S A. 2017 Jun 13;114(24):6292-6297
pubmed: 28559318
Biochemistry. 2011 Sep 27;50(38):8117-26
pubmed: 21848287
Mol Oncol. 2023 Apr;17(4):647-663
pubmed: 36744875
Expert Opin Drug Discov. 2015 May;10(5):449-61
pubmed: 25835573
Clin Pharmacokinet. 2018 Mar;57(3):315-333
pubmed: 29063518
J Biol Chem. 1998 Mar 6;273(10):5645-54
pubmed: 9488694
J Chem Theory Comput. 2013 Jul 9;9(7):3084-95
pubmed: 26583988
Biochemistry. 2007 Sep 18;46(37):10722-32
pubmed: 17715945
Int J Mol Sci. 2021 Jan 27;22(3):
pubmed: 33513969
J Biol Chem. 1996 Aug 9;271(32):19053-7
pubmed: 8702576
Cell. 2012 Mar 16;148(6):1204-22
pubmed: 22424230
Neurosciences (Riyadh). 2012 Oct;17(4):321-6
pubmed: 23022896
Proc Natl Acad Sci U S A. 2017 Jan 31;114(5):968-973
pubmed: 28096372
Proteins. 2008 Nov 15;73(3):765-83
pubmed: 18498103
J Chem Theory Comput. 2012 Sep 11;8(9):3314-21
pubmed: 26605738
Alzheimers Dement. 2023 Feb;19(2):658-670
pubmed: 35652476
Biochemistry. 2010 Nov 9;49(44):9533-41
pubmed: 20923231
J Mol Biol. 2006 Sep 1;361(5):932-44
pubmed: 16890957
Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501
pubmed: 20383002
J Chem Theory Comput. 2009 Jun 9;5(6):1632-9
pubmed: 26609855
J Prev Alzheimers Dis. 2016;3(4):219-228
pubmed: 29199323
Nat Aging. 2022 Apr;2(4):282-284
pubmed: 37117742
Alzheimers Dement. 2022 Apr;18(4):700-789
pubmed: 35289055
Nucleic Acids Res. 2019 Jan 8;47(D1):D442-D450
pubmed: 30395289
J Biol Chem. 2012 Feb 17;287(8):5253-66
pubmed: 22158868
Nat Med. 2018 May;24(5):647-657
pubmed: 29632371
J Biol Chem. 1994 Sep 2;269(35):22358-65
pubmed: 8071364
Transl Psychiatry. 2021 Mar 2;11(1):153
pubmed: 33654056
Annu Rev Neurosci. 1996;19:53-77
pubmed: 8833436
Alzheimers Dement (N Y). 2020 Dec 04;6(1):e12117
pubmed: 33304988
J Prev Alzheimers Dis. 2017;4(3):149-156
pubmed: 29182706
J Biol Chem. 2005 Dec 30;280(52):43236-42
pubmed: 16207708
Proc Natl Acad Sci U S A. 1994 Mar 1;91(5):1834-8
pubmed: 8127890
Biophys J. 2005 Jan;88(1):455-66
pubmed: 15475580
J Comput Chem. 2011 Aug;32(11):2359-68
pubmed: 21541964
Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):125-32
pubmed: 20124692
Biopolymers. 1983 Dec;22(12):2577-637
pubmed: 6667333
Neuron. 2022 Apr 20;110(8):1304-1317
pubmed: 35298921
Nucleic Acids Res. 2018 Jul 2;46(W1):W296-W303
pubmed: 29788355
Biochemistry. 2001 Mar 6;40(9):2826-34
pubmed: 11258893
J Chem Theory Comput. 2016 Apr 12;12(4):1845-52
pubmed: 26949976
Acta Crystallogr D Biol Crystallogr. 2013 Jul;69(Pt 7):1204-14
pubmed: 23793146
J Cheminform. 2012 Aug 13;4(1):17
pubmed: 22889332
Nucleic Acids Res. 2013 Jan;41(Database issue):D475-82
pubmed: 23193259
Nature. 2022 Nov;611(7937):769-779
pubmed: 36385529
J Biol Chem. 2005 Dec 30;280(52):43224-35
pubmed: 16207713
BMC Med. 2019 Mar 20;17(1):64
pubmed: 30890171
Alzheimers Dement (N Y). 2022 May 04;8(1):e12295
pubmed: 35516416
J Chem Phys. 2011 Feb 14;134(6):065101
pubmed: 21322734
Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2892-7
pubmed: 10694577
Biochim Biophys Acta. 2002 Sep 5;1584(1):9-19
pubmed: 12213488
Am J Pathol. 2022 Mar;192(3):564-578
pubmed: 34954207
J Clin Invest. 2018 May 1;128(5):2144-2155
pubmed: 29600961
J Neurosci. 2019 Nov 27;39(48):9611-9622
pubmed: 31641056
CNS Drugs. 2018 Sep;32(9):849-861
pubmed: 30076539
Neuron. 2017 Dec 6;96(5):1013-1023.e4
pubmed: 29216448
Brain Res. 1991 Feb 8;541(1):163-6
pubmed: 2029618
Cell Chem Biol. 2019 Jan 17;26(1):71-84.e4
pubmed: 30415965
Protein Sci. 2000 May;9(5):886-97
pubmed: 10850798
Biotechniques. 1990 Apr;8(4):404-7
pubmed: 2340178
CNS Drugs. 2017 Jun;31(6):495-509
pubmed: 28435985
Alzheimers Dement (N Y). 2021 May 25;7(1):e12185
pubmed: 34095442
J Appl Crystallogr. 2007 Aug 1;40(Pt 4):658-674
pubmed: 19461840
Cell Rep. 2022 Mar 1;38(9):110435
pubmed: 35235798
Alzheimers Dement. 2021 Apr;17(4):696-701
pubmed: 33135381
J Biol Chem. 2000 Nov 24;275(47):36758-65
pubmed: 10970893
Nat Methods. 2017 Jan;14(1):71-73
pubmed: 27819658
Biochemistry. 2006 Jan 17;45(2):381-90
pubmed: 16401069
Biochemistry. 2000 Sep 26;39(38):11657-66
pubmed: 10995233
J Biol Chem. 1998 Feb 13;273(7):4206-12
pubmed: 9461617
Neuropsychiatr Dis Treat. 2016 Jun 30;12:1589-98
pubmed: 27418826
Methods Enzymol. 2015;562:109-33
pubmed: 26412649