Methylation differences in Alzheimer's disease neuropathologic change in the aged human brain.
90 plus
AD
Alzheimer’s disease
Brain
Deconvolution
Gamma secretase
Methylation
Old age
PEN-2
Journal
Acta neuropathologica communications
ISSN: 2051-5960
Titre abrégé: Acta Neuropathol Commun
Pays: England
ID NLM: 101610673
Informations de publication
Date de publication:
29 11 2022
29 11 2022
Historique:
received:
23
09
2022
accepted:
24
10
2022
entrez:
30
11
2022
pubmed:
1
12
2022
medline:
2
12
2022
Statut:
epublish
Résumé
Alzheimer's disease (AD) is the most common cause of dementia with advancing age as its strongest risk factor. AD neuropathologic change (ADNC) is known to be associated with numerous DNA methylation changes in the human brain, but the oldest old (> 90 years) have so far been underrepresented in epigenetic studies of ADNC. Our study participants were individuals aged over 90 years (n = 47) from The 90+ Study. We analyzed DNA methylation from bulk samples in eight precisely dissected regions of the human brain: middle frontal gyrus, cingulate gyrus, entorhinal cortex, dentate gyrus, CA1, substantia nigra, locus coeruleus and cerebellar cortex. We deconvolved our bulk data into cell-type-specific (CTS) signals using computational methods. CTS methylation differences were analyzed across different levels of ADNC. The highest amount of ADNC related methylation differences was found in the dentate gyrus, a region that has so far been underrepresented in large scale multi-omic studies. In neurons of the dentate gyrus, DNA methylation significantly differed with increased burden of amyloid beta (Aβ) plaques at 5897 promoter regions of protein-coding genes. Amongst these, higher Aβ plaque burden was associated with promoter hypomethylation of the Presenilin enhancer 2 (PEN-2) gene, one of the rate limiting genes in the formation of gamma-secretase, a multicomponent complex that is responsible in part for the endoproteolytic cleavage of amyloid precursor protein into Aβ peptides. In addition to novel ADNC related DNA methylation changes, we present the most detailed array-based methylation survey of the old aged human brain to date. Our open-sourced dataset can serve as a brain region reference panel for future studies and help advance research in aging and neurodegenerative diseases.
Identifiants
pubmed: 36447297
doi: 10.1186/s40478-022-01470-0
pii: 10.1186/s40478-022-01470-0
pmc: PMC9710143
doi:
Substances chimiques
Amyloid beta-Peptides
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
174Subventions
Organisme : NIA NIH HHS
ID : U24 AG021886
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG066519
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG021055
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG066490
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH125244
Pays : United States
Organisme : NLM NIH HHS
ID : T15 LM007033
Pays : United States
Informations de copyright
© 2022. The Author(s).
Références
Nat Genet. 2009 Oct;41(10):1088-93
pubmed: 19734902
Nucleic Acids Res. 2015 Apr 20;43(7):e47
pubmed: 25605792
Genome Biol. 2016 Oct 7;17(1):208
pubmed: 27717381
BMC Bioinformatics. 2010 Nov 30;11:587
pubmed: 21118553
Alzheimers Dement. 2018 Dec;14(12):1580-1588
pubmed: 29550519
Genome Med. 2016 Jan 19;8(1):5
pubmed: 26803900
Nat Genet. 2022 Apr;54(4):412-436
pubmed: 35379992
Sci Aging Knowledge Environ. 2003 Mar 19;2003(11):PE7
pubmed: 12844518
Bioinformatics. 2013 Jan 15;29(2):189-96
pubmed: 23175756
Front Neuroanat. 2018 Oct 30;12:90
pubmed: 30425626
Clin Epigenetics. 2019 Jun 19;11(1):91
pubmed: 31217032
Nat Genet. 2013 Dec;45(12):1452-8
pubmed: 24162737
Neurobiol Aging. 2020 Nov;95:15-25
pubmed: 32745806
Nat Protoc. 2009;4(8):1184-91
pubmed: 19617889
J Psychiatr Res. 1975 Nov;12(3):189-98
pubmed: 1202204
Nat Neurosci. 2019 Feb;22(2):307-316
pubmed: 30643296
Nat Neurosci. 2014 Sep;17(9):1164-70
pubmed: 25129077
J Gerontol. 1982 May;37(3):323-9
pubmed: 7069156
Epigenetics. 2013 Mar;8(3):290-302
pubmed: 23426267
Curr Alzheimer Res. 2012 Jul;9(6):709-17
pubmed: 22471863
Clin Epigenetics. 2019 Mar 21;11(1):52
pubmed: 30898171
Bioinformatics. 2014 May 15;30(10):1363-9
pubmed: 24478339
Neurology. 1991 Apr;41(4):479-86
pubmed: 2011243
Neuropathology. 2015 Aug;35(4):354-89
pubmed: 25619230
Nat Rev Mol Cell Biol. 2011 Jul 22;12(8):517-33
pubmed: 21779028
Nat Commun. 2021 Jun 10;12(1):3517
pubmed: 34112773
Nat Genet. 2022 Jan;54(1):4-17
pubmed: 34992268
J Gerontol A Biol Sci Med Sci. 2018 Mar 2;73(3):289-298
pubmed: 28655199
Acta Neuropathol. 2019 Apr;137(4):557-569
pubmed: 30712078
Nat Commun. 2022 Sep 24;13(1):5620
pubmed: 36153390
PLoS Med. 2017 Mar 28;14(3):e1002270
pubmed: 28350801
Sci Rep. 2019 Aug 19;9(1):11960
pubmed: 31427598
Biochem Biophys Res Commun. 2011 Dec 2;415(4):656-61
pubmed: 22079091
Hum Mol Genet. 2017 Oct 1;26(R2):R216-R224
pubmed: 28977446
Nat Methods. 2022 Mar;19(3):296-306
pubmed: 35277705
Nat Clin Pract Oncol. 2005 Dec;2 Suppl 1:S4-11
pubmed: 16341240
Acta Biochim Biophys Sin (Shanghai). 2015 Apr;47(4):258-66
pubmed: 25736404
Science. 2020 Sep 11;369(6509):1318-1330
pubmed: 32913098
Histochem Cell Biol. 2019 Jan;151(1):91-96
pubmed: 30357509
Nat Commun. 2019 Jul 31;10(1):3417
pubmed: 31366909
J Neurochem. 2006 Mar;96(5):1423-40
pubmed: 16464238
Acta Neuropathol Commun. 2022 Jan 8;10(1):4
pubmed: 34998435
J Neurol. 2005 Sep;252(9):1033-6
pubmed: 16170650
Epigenetics Chromatin. 2018 Jul 25;11(1):41
pubmed: 30045751
Nucleic Acids Res. 2015 Jan;43(2):732-44
pubmed: 25572316
Clin Epigenetics. 2019 Nov 27;11(1):164
pubmed: 31775875
J Biol Chem. 2003 Mar 7;278(10):7850-4
pubmed: 12522139
Nat Neurosci. 2014 Sep;17(9):1156-63
pubmed: 25129075
Acta Neuropathol. 2013 Jun;125(6):861-78
pubmed: 23589030
Neurobiol Aging. 2013 Sep;34(9):2091-9
pubmed: 23582657
Nat Genet. 2020 Nov;52(11):1158-1168
pubmed: 33106633
Acta Neuropathol. 2001 Mar;101(3):249-55
pubmed: 11307625
Neuron. 2008 Apr 10;58(1):42-51
pubmed: 18400162
Alzheimer Dis Assoc Disord. 1996 Spring;10(1):31-9
pubmed: 8919494
J Comp Neurol. 2016 Dec 15;524(18):3865-3895
pubmed: 27187682
CNS Neurosci Ther. 2021 Feb;27(2):174-185
pubmed: 32961023
Annu Rev Cell Dev Biol. 2012;28:309-36
pubmed: 22831640
Genom Data. 2016 May 26;9:22-4
pubmed: 27330998
Arch Neurol. 1994 Sep;51(9):901-6
pubmed: 8080390
Bioinformatics. 2017 Feb 15;33(4):558-560
pubmed: 28035024
Gigascience. 2020 May 1;9(5):
pubmed: 32401319
Alzheimers Dement. 2012 Jan;8(1):1-13
pubmed: 22265587
Acta Neuropathol. 2012 Jan;123(1):1-11
pubmed: 22101365
Front Genet. 2015 May 18;6:182
pubmed: 26042147
Brain. 2013 Dec;136(Pt 12):3738-52
pubmed: 24136825
Aging Dis. 2020 Mar 9;11(2):390-404
pubmed: 32257549
Mol Psychiatry. 2013 Nov;18(11):1225-34
pubmed: 23399914
Front Neurosci. 2019 May 16;13:463
pubmed: 31156365
Nat Biotechnol. 2009 Apr;27(4):361-8
pubmed: 19329998
Brain. 2020 Dec 1;143(12):3763-3775
pubmed: 33300551
Genome Biol. 2019 Mar 14;20(1):55
pubmed: 30871603
Neuron. 2003 Apr 10;38(1):9-12
pubmed: 12691659
Bioinformatics. 2017 Dec 15;33(24):3982-3984
pubmed: 28961746
Exp Mol Med. 2022 Apr;54(4):433-446
pubmed: 35396575
Alzheimers Dement. 2016 Aug;12(8):900-8
pubmed: 27243907
Nature. 2003 Mar 27;422(6930):438-41
pubmed: 12660785
J Alzheimers Dis. 2019;71(3):751-761
pubmed: 31450497