MFG-E8 (LACTADHERIN): a novel marker associated with cerebral amyloid angiopathy.
Alzheimer's disease
Biomarkers
Cerebral amyloid angiopathy
Cerebrospinal fluid
Laser capture microdissection
MFG-E8
Journal
Acta neuropathologica communications
ISSN: 2051-5960
Titre abrégé: Acta Neuropathol Commun
Pays: England
ID NLM: 101610673
Informations de publication
Date de publication:
16 09 2021
16 09 2021
Historique:
received:
02
09
2021
accepted:
04
09
2021
entrez:
17
9
2021
pubmed:
18
9
2021
medline:
27
1
2022
Statut:
epublish
Résumé
Brain accumulation of amyloid-beta (Aβ) is a crucial feature in Alzheimer´s disease (AD) and cerebral amyloid angiopathy (CAA), although the pathophysiological relationship between these diseases remains unclear. Numerous proteins are associated with Aβ deposited in parenchymal plaques and/or cerebral vessels. We hypothesized that the study of these proteins would increase our understanding of the overlap and biological differences between these two pathologies and may yield new diagnostic tools and specific therapeutic targets. We used a laser capture microdissection approach combined with mass spectrometry in the APP23 transgenic mouse model of cerebral-β-amyloidosis to specifically identify vascular Aβ-associated proteins. We focused on one of the main proteins detected in the Aβ-affected cerebrovasculature: MFG-E8 (milk fat globule-EGF factor 8), also known as lactadherin. We first validated the presence of MFG-E8 in mouse and human brains. Immunofluorescence and immunoblotting studies revealed that MFG-E8 brain levels were higher in APP23 mice than in WT mice. Furthermore, MFG-E8 was strongly detected in Aβ-positive vessels in human postmortem CAA brains, whereas MFG-E8 was not present in parenchymal Aβ deposits. Levels of MFG-E8 were additionally analysed in serum and cerebrospinal fluid (CSF) from patients diagnosed with CAA, patients with AD and control subjects. Whereas no differences were found in MFG-E8 serum levels between groups, MFG-E8 concentration was significantly lower in the CSF of CAA patients compared to controls and AD patients. Finally, in human vascular smooth muscle cells MFG-E8 was protective against the toxic effects of the treatment with the Aβ40 peptide containing the Dutch mutation. In summary, our study shows that MFG-E8 is highly associated with CAA pathology and highlights MFG-E8 as a new CSF biomarker that could potentially be used to differentiate cerebrovascular Aβ pathology from parenchymal Aβ deposition.
Identifiants
pubmed: 34530925
doi: 10.1186/s40478-021-01257-9
pii: 10.1186/s40478-021-01257-9
pmc: PMC8444498
doi:
Substances chimiques
Antigens, Surface
0
Biomarkers
0
Mfge8 protein, mouse
0
Milk Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
154Subventions
Organisme : NINDS NIH HHS
ID : R01 NS104147
Pays : United States
Informations de copyright
© 2021. The Author(s).
Références
Neurology. 1991 Apr;41(4):479-86
pubmed: 2011243
Eur J Neurol. 2018 Jan;25(1):59-70
pubmed: 28872215
Brain. 2017 Jul 1;140(7):1829-1850
pubmed: 28334869
J Leukoc Biol. 2008 May;83(5):1300-7
pubmed: 18303131
Alzheimers Dement. 2011 May;7(3):263-9
pubmed: 21514250
PLoS One. 2015 Apr 13;10(4):e0122833
pubmed: 25867181
Proc Natl Acad Sci U S A. 1996 Apr 2;93(7):2996-3000
pubmed: 8610157
J Neuroimmune Pharmacol. 2008 Dec;3(4):246-56
pubmed: 18670887
Acta Neuropathol Commun. 2020 Jul 6;8(1):99
pubmed: 32631441
Nature. 2002 May 9;417(6885):182-7
pubmed: 12000961
J Neuropathol Exp Neurol. 2002 Mar;61(3):282-93
pubmed: 11895043
Front Neurol. 2019 Mar 13;10:187
pubmed: 30918495
Acta Neuropathol. 2009 Jul;118(1):115-30
pubmed: 19225789
Semin Neurol. 2016 Jun;36(3):233-43
pubmed: 27214698
Science. 2004 May 21;304(5674):1147-50
pubmed: 15155946
Lancet Neurol. 2016 Jun;15(7):673-684
pubmed: 27068280
Acta Neuropathol Commun. 2018 Jun 4;6(1):46
pubmed: 29860944
J Neurosci. 2012 Feb 22;32(8):2657-66
pubmed: 22357850
Cell Death Differ. 2017 Feb;24(2):263-275
pubmed: 27768123
Ann Neurol. 2011 Feb;69(2):320-7
pubmed: 21387377
Neuropharmacology. 2012 Feb;62(2):890-900
pubmed: 21964436
Nat Med. 2005 May;11(5):499-506
pubmed: 15834428
Alzheimers Dement. 2019 Mar;15(3):429-440
pubmed: 30502339
Acta Neuropathol Commun. 2019 Jan 28;7(1):12
pubmed: 30691533
Front Neurol. 2018 Feb 26;9:96
pubmed: 29535679
Neuropathol Appl Neurobiol. 2020 Aug;46(5):431-440
pubmed: 31872472
Circ Res. 2009 Jun 19;104(12):1337-46
pubmed: 19443842
Ann Neurol. 2011 Dec;70(6):871-80
pubmed: 22190361
Ann Neurol. 2009 Aug;66(2):245-9
pubmed: 19743453
Blood. 2009 Feb 5;113(6):1332-9
pubmed: 19023116
J Neurol Neurosurg Psychiatry. 2007 Aug;78(8):836-40
pubmed: 17220294
Lupus. 2014 Apr;23(4):386-94
pubmed: 24554711
J Dermatol. 2017 Jul;44(7):783-788
pubmed: 28266034
Curr Vasc Pharmacol. 2013 Sep;11(5):768-76
pubmed: 22272902
Nat Rev Neurol. 2015 Aug;11(8):457-70
pubmed: 26195256
Neurology. 2010 Apr 27;74(17):1346-50
pubmed: 20421578
Neurology. 2004 Nov 9;63(9):1606-12
pubmed: 15534243
Alzheimers Dement (Amst). 2020 Aug 25;12(1):e12072
pubmed: 32875054
Stroke. 1987 Mar-Apr;18(2):311-24
pubmed: 3551211
Proc Natl Acad Sci U S A. 2020 Sep 22;117(38):23925-23931
pubmed: 32900929
J Am Heart Assoc. 2020 Jan 21;9(2):e014810
pubmed: 31928157
Arch Neurol. 2009 Mar;66(3):382-9
pubmed: 19273758
Ageing Res Rev. 2020 Dec;64:101176
pubmed: 32971257
J Clin Invest. 2013 Mar;123(3):1176-81
pubmed: 23454767
Acta Neuropathol. 2006 Oct;112(4):389-404
pubmed: 16906426
Am J Pathol. 2014 Jul;184(7):1981-90
pubmed: 24838098
J Neuroinflammation. 2006 Aug 03;3:18
pubmed: 16887032
Stroke. 1997 Jul;28(7):1418-22
pubmed: 9227694
J Biomed Sci. 2019 Aug 30;26(1):61
pubmed: 31470852
Acta Neuropathol. 2017 Jun;133(6):933-954
pubmed: 28258398
Exp Neurol. 2021 Feb;336:113532
pubmed: 33245889
Nat Rev Neurol. 2020 Jan;16(1):30-42
pubmed: 31827267
Neurology. 2018 Feb 27;90(9):e754-e762
pubmed: 29386280
J Neurochem. 1996 Jun;66(6):2429-35
pubmed: 8632166
Cardiovasc Res. 2017 Sep 01;113(11):1389-1402
pubmed: 28859297
Acta Neuropathol. 1998 Dec;96(6):628-36
pubmed: 9845293
Alzheimers Dement. 2022 Jan;18(1):10-28
pubmed: 34057813
Blood. 2018 Feb 1;131(5):563-572
pubmed: 29162596
Am J Pathol. 1994 Aug;145(2):452-60
pubmed: 8053502
Annu Rev Pathol. 2015;10:291-319
pubmed: 25387055
Acta Neuropathol. 1994;88(4):371-8
pubmed: 7839831
Acta Neuropathol. 2017 Oct;134(4):605-617
pubmed: 28478503
J Korean Neurosurg Soc. 2020 Mar;63(2):163-170
pubmed: 32120456
Am J Pathol. 2007 Mar;170(3):921-9
pubmed: 17322377
Neuropathol Appl Neurobiol. 2017 Oct;43(6):492-504
pubmed: 27543695
Aging Cell. 2012 Jun;11(3):500-8
pubmed: 22385834
Cell Death Dis. 2018 Aug 28;9(9):845
pubmed: 30154436
Alzheimers Dement. 2012 Jan;8(1):1-13
pubmed: 22265587
J Neuroinflammation. 2012 Jun 28;9:148
pubmed: 22742657
Geriatr Gerontol Int. 2019 Oct;19(10):1054-1062
pubmed: 31436032
DNA Cell Biol. 1997 Jul;16(7):861-9
pubmed: 9260929
Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):13287-92
pubmed: 9371838
Neurology. 2012 May 15;78(20):1568-75
pubmed: 22517093