Proteomic alterations in the brain and blood-brain barrier during brain Aβ accumulation in an APP knock-in mouse model of Alzheimer's disease.
Alzheimer’s disease
Amyloid-β peptide
Apolipoprotein
Basement membrane
Blood–brain barrier
Proteome analysis
Journal
Fluids and barriers of the CNS
ISSN: 2045-8118
Titre abrégé: Fluids Barriers CNS
Pays: England
ID NLM: 101553157
Informations de publication
Date de publication:
14 Sep 2023
14 Sep 2023
Historique:
received:
04
04
2023
accepted:
02
09
2023
medline:
15
9
2023
pubmed:
14
9
2023
entrez:
13
9
2023
Statut:
epublish
Résumé
Blood-brain barrier (BBB) dysfunction is supposed to be an early event in the development of Alzheimer's disease (AD). This study aimed to investigate the relationship between BBB alterations and AD progression in terms of amyloid-β peptide (Aβ) accumulation in the brains of humanized amyloid precursor protein knock-in (APP-KI) mice. Brain Aβ accumulation was examined using immunohistochemical analysis. Alterations in differentially expressed proteins were determined using sequential window acquisition of all theoretical fragment ion mass spectroscopy (SWATH-MS)-based quantitative proteomics, and Metascape, STRING, Gene Ontology, and KEGG were used for network analyses of altered biological pathways and processes. Statistical significance was determined using the unpaired two-tailed Student's t-test and Welch's t-test for two groups and one-way analysis of variance followed by Tukey's test for more than two groups. Correlations between two groups were determined using Pearson's correlation analysis. Brain Aβ accumulation in APP-KI mice was detectable at 2 months, increased significantly at 5 months, and remained elevated at 12 months of age. The levels of differentially expressed proteins in isolated brain capillaries were higher in younger mice, whereas those in the brain were higher in older mice. Network analyses indicated changes in basement membrane-associated and ribosomal proteins in the brain capillaries. There were no significant changes in key proteins involved in drug or Aβ transport at the BBB. In contrast, solute carrier transporter levels in astrocytes, microglia, and neurons were altered in the brain of older mice. Moreover, the levels of the lipid transporters Apoe and Apoj were upregulated in both the brain and isolated brain capillaries after Aβ accumulation. Our results suggest that changes in the brain occurred after advanced Aβ accumulation, whereas initial Aβ accumulation was sufficient to cause alterations in the BBB. These findings may help elucidate the role of BBB alterations in AD progression and predict the distribution of drugs across the BBB in the brain of patients with AD.
Sections du résumé
BACKGROUND
BACKGROUND
Blood-brain barrier (BBB) dysfunction is supposed to be an early event in the development of Alzheimer's disease (AD). This study aimed to investigate the relationship between BBB alterations and AD progression in terms of amyloid-β peptide (Aβ) accumulation in the brains of humanized amyloid precursor protein knock-in (APP-KI) mice.
METHODS
METHODS
Brain Aβ accumulation was examined using immunohistochemical analysis. Alterations in differentially expressed proteins were determined using sequential window acquisition of all theoretical fragment ion mass spectroscopy (SWATH-MS)-based quantitative proteomics, and Metascape, STRING, Gene Ontology, and KEGG were used for network analyses of altered biological pathways and processes. Statistical significance was determined using the unpaired two-tailed Student's t-test and Welch's t-test for two groups and one-way analysis of variance followed by Tukey's test for more than two groups. Correlations between two groups were determined using Pearson's correlation analysis.
RESULTS
RESULTS
Brain Aβ accumulation in APP-KI mice was detectable at 2 months, increased significantly at 5 months, and remained elevated at 12 months of age. The levels of differentially expressed proteins in isolated brain capillaries were higher in younger mice, whereas those in the brain were higher in older mice. Network analyses indicated changes in basement membrane-associated and ribosomal proteins in the brain capillaries. There were no significant changes in key proteins involved in drug or Aβ transport at the BBB. In contrast, solute carrier transporter levels in astrocytes, microglia, and neurons were altered in the brain of older mice. Moreover, the levels of the lipid transporters Apoe and Apoj were upregulated in both the brain and isolated brain capillaries after Aβ accumulation.
CONCLUSIONS
CONCLUSIONS
Our results suggest that changes in the brain occurred after advanced Aβ accumulation, whereas initial Aβ accumulation was sufficient to cause alterations in the BBB. These findings may help elucidate the role of BBB alterations in AD progression and predict the distribution of drugs across the BBB in the brain of patients with AD.
Identifiants
pubmed: 37705104
doi: 10.1186/s12987-023-00466-9
pii: 10.1186/s12987-023-00466-9
pmc: PMC10500766
doi:
Substances chimiques
Membrane Transport Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
66Informations de copyright
© 2023. BioMed Central Ltd., part of Springer Nature.
Références
Neuron. 2015 Jan 21;85(2):296-302
pubmed: 25611508
EMBO Mol Med. 2021 Feb 5;13(2):e12632
pubmed: 33428810
N Engl J Med. 2006 Apr 6;354(14):1489-96
pubmed: 16598045
Nat Rev Mol Cell Biol. 2007 Feb;8(2):101-12
pubmed: 17245412
J Cereb Blood Flow Metab. 2017 Oct;37(10):3300-3317
pubmed: 28753105
Curr Biol. 2016 Sep 12;26(17):2291-300
pubmed: 27524482
Nat Commun. 2019 Apr 3;10(1):1523
pubmed: 30944313
Exp Neurol. 1996 Mar;138(1):22-32
pubmed: 8593893
Drug Metab Dispos. 2010 Jan;38(1):168-76
pubmed: 19833843
Neurobiol Learn Mem. 2016 Nov;135:73-82
pubmed: 27377630
J Neurochem. 2007 Dec;103(6):2482-90
pubmed: 17908238
Cell Rep Med. 2020 Nov 17;1(8):100138
pubmed: 33294859
Clin Psychopharmacol Neurosci. 2020 May 31;18(2):174-187
pubmed: 32329299
Neuro Endocrinol Lett. 2004 Dec;25(6):435-7
pubmed: 15665806
PLoS One. 2012;7(5):e36893
pubmed: 22615835
Nature. 2020 May;581(7806):71-76
pubmed: 32376954
Alzheimers Dement. 2017 Oct;13(10):1143-1153
pubmed: 28343848
J Neurosci. 2014 Sep 3;34(36):11929-47
pubmed: 25186741
J Clin Invest. 2005 Nov;115(11):3285-90
pubmed: 16239972
J Cereb Blood Flow Metab. 2021 May;41(5):1026-1038
pubmed: 32703112
Elife. 2019 Nov 18;8:
pubmed: 31738162
Nat Commun. 2016 Jun 21;7:11934
pubmed: 27327500
Brain Res. 2010 Oct 28;1358:228-38
pubmed: 20727860
Brain Behav Immun. 2018 Oct;73:21-33
pubmed: 30041013
Dev Med Child Neurol. 2007 Sep;49(9):707-16
pubmed: 17718830
Neuron. 2013 Dec 18;80(6):1347-58
pubmed: 24360540
FEBS Lett. 2019 Jun;593(11):1144-1153
pubmed: 31058310
Science. 2005 May 20;308(5725):1167-71
pubmed: 15905400
Nat Med. 2019 Feb;25(2):270-276
pubmed: 30643288
Eur J Nucl Med Mol Imaging. 2009 May;36(5):811-22
pubmed: 19142633
J Clin Invest. 2000 Dec;106(12):1489-99
pubmed: 11120756
Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):15233-8
pubmed: 10611368
Neurochem Int. 2001 Nov-Dec;39(5-6):415-25
pubmed: 11578777
Mol Pharm. 2013 Jan 7;10(1):289-96
pubmed: 23137377
Fluids Barriers CNS. 2013 Jun 08;10(1):21
pubmed: 23758935
Alzheimers Dement. 2019 Dec;15(12):1568-1575
pubmed: 31862169
Development. 2004 Apr;131(7):1619-28
pubmed: 14998921
Brain Res. 2006 Dec 6;1123(1):245-52
pubmed: 17074306
J Biol Chem. 2004 Sep 24;279(39):41197-207
pubmed: 15269218
J Neuroimmunol. 2001 Mar 1;114(1-2):168-72
pubmed: 11240028
Lancet Neurol. 2006 Jan;5(1):64-74
pubmed: 16361024
NeuroRx. 2005 Jan;2(1):86-98
pubmed: 15717060
Jpn J Psychiatry Neurol. 1991 Sep;45(3):671-6
pubmed: 1800815
Pflugers Arch. 2004 Feb;447(5):469-79
pubmed: 14530974
Nat Commun. 2013;4:2932
pubmed: 24336108
Theranostics. 2017 Jan 1;7(2):308-318
pubmed: 28042336
Neurobiol Aging. 2007 Jul;28(7):977-86
pubmed: 16782234
Neurobiol Dis. 2010 Feb;37(2):423-33
pubmed: 19879361
Nat Rev Cancer. 2020 Jan;20(1):26-41
pubmed: 31601988
Nat Commun. 2017 Oct 17;8(1):1001
pubmed: 29042554
JAMA Neurol. 2013 Mar 1;70(3):320-5
pubmed: 23599929
J Cereb Blood Flow Metab. 2022 Nov;42(11):2134-2150
pubmed: 35766008
Brain. 2019 Apr 1;142(4):1077-1092
pubmed: 30770921
Neurology. 2013 Jan 22;80(4):359-65
pubmed: 23255822
Eur J Nucl Med Mol Imaging. 2005 Apr;32(4):486-510
pubmed: 15747152
J Proteome Res. 2008 Feb;7(2):731-40
pubmed: 18183947
Ann N Y Acad Sci. 1997 Sep 26;826:147-60
pubmed: 9329687
Nat Neurosci. 2014 May;17(5):661-3
pubmed: 24728269
Proc Natl Acad Sci U S A. 2011 Apr 5;108(14):5819-24
pubmed: 21421841
Pharm Res. 2008 Jun;25(6):1469-83
pubmed: 18219561
EMBO J. 2001 Dec 17;20(24):7041-51
pubmed: 11742981
Nat Methods. 2020 Jan;17(1):41-44
pubmed: 31768060
J Neurosci. 2009 Apr 29;29(17):5463-75
pubmed: 19403814
J Alzheimers Dis. 2014;38(1):185-200
pubmed: 23948938
J Pharm Sci. 2017 Sep;106(9):2599-2605
pubmed: 28456720
J Neurochem. 2008 Aug;106(4):1534-44
pubmed: 18489712
Transl Psychiatry. 2015 May 05;5:e561
pubmed: 25942042
Fluids Barriers CNS. 2012 Nov 09;9(1):23
pubmed: 23140302
Mol Imaging Biol. 2012 Dec;14(6):771-6
pubmed: 22476967
Pharm Res. 2019 Jul 31;36(10):141
pubmed: 31367840
Pflugers Arch. 2016 Feb;468(2):213-27
pubmed: 26490457
J Neurosci. 2016 Feb 10;36(6):1930-41
pubmed: 26865616
Sci Transl Med. 2021 Feb 17;13(581):
pubmed: 33597265
Nature. 2010 Nov 25;468(7323):562-6
pubmed: 20944625
Life Sci. 2009 Dec 16;85(23-26):775-81
pubmed: 19891976
Mol Ther. 2018 May 2;26(5):1366-1374
pubmed: 29606503
Pharm Res. 1995 Jun;12(6):807-16
pubmed: 7667183
J Cereb Blood Flow Metab. 2003 Apr;23(4):432-40
pubmed: 12679720
Pharmacogenetics. 2002 Oct;12(7):535-41
pubmed: 12360104
Eur J Pharmacol. 2007 Apr 30;561(1-3):226-32
pubmed: 17349620
J Neurochem. 2002 Apr;81(1):203-6
pubmed: 12067234
J Clin Invest. 2016 Jan;126(1):123-36
pubmed: 26619118
Pharm Res. 2022 Jul;39(7):1561-1574
pubmed: 34811625