Oxidative Damage and Antioxidant Response in Frontal Cortex of Demented and Nondemented Individuals with Alzheimer's Neuropathology.
Aged
Aged, 80 and over
Alzheimer Disease
/ metabolism
Amyloid beta-Peptides
/ metabolism
Antioxidants
/ metabolism
Astrocytes
/ enzymology
Autopsy
Dementia
/ metabolism
Female
Free Radical Scavengers
/ metabolism
Humans
Male
MicroRNAs
/ genetics
Neurons
/ enzymology
Oxidation-Reduction
Oxidative Stress
PPAR gamma
/ genetics
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
/ genetics
Prefrontal Cortex
/ metabolism
Alzheimer's disease
NDAN
PGC1α
PPARα
miRNA-485
oxidative stress
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
ISSN: 1529-2401
Titre abrégé: J Neurosci
Pays: United States
ID NLM: 8102140
Informations de publication
Date de publication:
20 01 2021
20 01 2021
Historique:
received:
05
02
2020
revised:
05
10
2020
accepted:
07
10
2020
pubmed:
27
11
2020
medline:
30
3
2021
entrez:
26
11
2020
Statut:
ppublish
Résumé
Alzheimer's disease (AD) is characterized by progressive neurodegeneration in the cerebral cortex, histopathologically hallmarked by amyloid β (Aβ) extracellular plaques and intracellular neurofibrillary tangles, constituted by hyperphosphorylated tau protein. Correlation between these pathologic features and dementia has been challenged by the emergence of "nondemented with Alzheimer's neuropathology" (NDAN) individuals, cognitively intact despite displaying pathologic features of AD. The existence of these subjects suggests that some unknown mechanisms are triggered to resist Aβ-mediated detrimental events. Aβ accumulation affects mitochondrial redox balance, increasing oxidative stress status, which in turn is proposed as a primary culprit in AD pathogenesis. To clarify the relationship linking Aβ, oxidative stress, and cognitive impairment, we performed a comparative study on AD, NDAN, and aged-matched human postmortem frontal cortices of either sex. We quantitatively analyzed immunofluorescence distribution of oxidative damage markers, and of SOD2 (superoxide dismutase 2), PGC1α [peroxisome proliferator-activated receptor (PPAR) γ-coactivator 1α], PPARα, and catalase as key factors in antioxidant response, as well as the expression of miRNA-485, as a PGC1α upstream regulator. Our results confirm dramatic redox imbalance, associated with impaired antioxidant defenses in AD brain. By contrast, NDAN individuals display low oxidative damage, which is associated with high levels of scavenging systems, possibly resulting from a lack of PGC1α miRNA-485-related inhibition. Comparative analyses in neurons and astrocytes further highlighted cell-specific mechanisms to counteract redox imbalance. Overall, our data emphasize the importance of transcriptional and post-transcriptional regulation of antioxidant response in AD. This suggests that an efficient PGC1α-dependent "safety mechanism" may prevent Aβ-mediated oxidative stress, supporting neuroprotective therapies aimed at ameliorating defects in antioxidant response pathways in AD patients.
Identifiants
pubmed: 33239403
pii: JNEUROSCI.0295-20.2020
doi: 10.1523/JNEUROSCI.0295-20.2020
pmc: PMC7821866
doi:
Substances chimiques
Amyloid beta-Peptides
0
Antioxidants
0
Free Radical Scavengers
0
MIRN485 microRNA, human
0
MicroRNAs
0
PPAR gamma
0
PPARGC1A protein, human
0
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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
538-554Subventions
Organisme : NIA NIH HHS
ID : P30 AG008017
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG042890
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG060718
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG060718
Pays : United States
Informations de copyright
Copyright © 2021 Fracassi et al.
Déclaration de conflit d'intérêts
The authors declare no competing financial interests.
Références
Oxid Med Cell Longev. 2013;2013:316523
pubmed: 23983897
Biochim Biophys Acta. 2000 Jul 26;1502(1):139-44
pubmed: 10899439
Prog Neurobiol. 2016 Dec;147:1-19
pubmed: 27769868
Biomed Rep. 2016 May;4(5):519-522
pubmed: 27123241
Free Radic Biol Med. 2017 Oct;111:253-261
pubmed: 27789292
Ann Neurol. 1994 Nov;36(5):747-51
pubmed: 7979220
Mutat Res. 2000 Mar 17;448(2):159-77
pubmed: 10725470
Alzheimers Dement. 2018 Apr;14(4):535-562
pubmed: 29653606
Biomed Res Int. 2014;2014:175062
pubmed: 24900954
Front Cell Dev Biol. 2016 Jan 28;3:83
pubmed: 26858947
Alzheimers Dement. 2017 Jul;13(7):810-827
pubmed: 28242299
J Alzheimers Dis. 2013;33 Suppl 1:S243-51
pubmed: 22683528
J Alzheimers Dis. 2009;18(4):935-52
pubmed: 19749434
Ann Neurosci. 2017 May;24(1):46-54
pubmed: 28588356
Nat Chem Biol. 2016 Dec;12(12):1075-1083
pubmed: 27748752
J Extracell Vesicles. 2019 Jun 17;8(1):1626654
pubmed: 31258880
EMBO Mol Med. 2016 Jun 01;8(6):595-608
pubmed: 27025652
Sci Rep. 2017 Nov 8;7(1):15012
pubmed: 29118388
IUBMB Life. 2012 Dec;64(12):958-64
pubmed: 23129362
Trends Mol Med. 2001 Dec;7(12):548-54
pubmed: 11733217
PLoS One. 2016 Sep 09;11(9):e0162628
pubmed: 27611371
Exp Neurobiol. 2015 Dec;24(4):325-40
pubmed: 26713080
Biochem Soc Trans. 2014 Oct;42(5):1316-20
pubmed: 25233409
Curr Med Chem. 2014;21(24):2803-21
pubmed: 24606520
Behav Brain Res. 2008 Sep 1;192(1):106-13
pubmed: 18359102
Plant Cell Physiol. 2016 Jul;57(7):1364-1376
pubmed: 27081099
Prog Lipid Res. 2006 Mar;45(2):120-59
pubmed: 16476485
Sci Transl Med. 2011 Apr 6;3(77):77sr1
pubmed: 21471435
Mol Neurodegener. 2013 Feb 02;8:8
pubmed: 23374228
Science. 1992 Apr 10;256(5054):184-5
pubmed: 1566067
Free Radic Biol Med. 1997;23(1):134-47
pubmed: 9165306
Antioxid Redox Signal. 2013 Feb 1;18(4):386-99
pubmed: 22861165
Anat Cell Biol. 2016 Mar;49(1):1-6
pubmed: 27051562
Chem Res Toxicol. 2008 Jan;21(1):172-88
pubmed: 18052107
Biochim Biophys Acta. 2014 Aug;1842(8):1167
pubmed: 24686117
Redox Biol. 2018 Apr;14:450-464
pubmed: 29080524
Front Mol Neurosci. 2017 Dec 19;10:427
pubmed: 29311817
Oxid Med Cell Longev. 2015;2015:504678
pubmed: 26301043
N Engl J Med. 2010 Jan 28;362(4):329-44
pubmed: 20107219
J Biol Chem. 2005 Dec 23;280(51):41921-7
pubmed: 16219762
J Neurochem. 1995 Nov;65(5):2146-56
pubmed: 7595501
Arch Neurol. 2009 Mar;66(3):352-61
pubmed: 19273754
Prog Neurobiol. 2016 Sep;144:121-41
pubmed: 26797041
J Alzheimers Dis. 2018;62(3):1403-1416
pubmed: 29036828
Nat Neurosci. 2015 Jun;18(6):800-6
pubmed: 26007213
J Alzheimers Dis. 2013;33(4):941-59
pubmed: 23109558
Br J Pharmacol. 2019 Sep;176(18):3489-3507
pubmed: 30675901
Sci Rep. 2019 Jun 3;9(1):8228
pubmed: 31160730
World J Biol Chem. 2015 Nov 26;6(4):301-9
pubmed: 26629313
Neurobiol Aging. 2019 Nov;83:124-129
pubmed: 31732015
Clin Chim Acta. 2016 May 1;456:107-114
pubmed: 26944571
Biochim Biophys Acta. 2014 Aug;1842(8):1240-7
pubmed: 24189435
J Alzheimers Dis. 2017;57(4):1105-1121
pubmed: 28059794
J Neurosci Methods. 2016 Mar 1;261:128-34
pubmed: 26774027
Free Radic Biol Med. 2013 Sep;62:4-12
pubmed: 23727323
J Neurochem. 2001 Jul;78(2):413-6
pubmed: 11461977
EBioMedicine. 2016 Apr;6:42-49
pubmed: 27211547
Science. 1996 Oct 4;274(5284):99-102
pubmed: 8810256
Oxid Med Cell Longev. 2015;2015:967203
pubmed: 25973140
J Biol Chem. 2005 Dec 9;280(49):41057-68
pubmed: 16204253
Proc Natl Acad Sci U S A. 2010 Nov 23;107(47):20376-81
pubmed: 21059926
Sci Rep. 2016 Jun 14;6:27812
pubmed: 27298190
Cell. 2006 Oct 20;127(2):397-408
pubmed: 17055439
Cell Tissue Res. 2015 Aug;361(2):593-604
pubmed: 25722086
Neurosci Bull. 2014 Apr;30(2):243-52
pubmed: 24733654
Redox Biol. 2019 Jun;24:101167
pubmed: 30921635
Antioxid Redox Signal. 2009 Mar;11(3):509-28
pubmed: 18717631
Mol Neurodegener. 2012 May 28;7:23
pubmed: 22640423
Curr Alzheimer Res. 2018;15(8):764-776
pubmed: 29473507
Mitochondrion. 2013 Mar;13(2):134-42
pubmed: 23347985
World J Cardiol. 2013 Jun 26;5(6):164-74
pubmed: 23802046
J Aging Res. 2011;2011:810619
pubmed: 21629705
Cell Death Dis. 2016 Mar 24;7:e2159
pubmed: 27010860
J Alzheimers Dis. 2017;57(4):1087-1103
pubmed: 27767992
J Cell Sci. 2012 Nov 1;125(Pt 21):4963-71
pubmed: 23277535
Mol Neurodegener. 2019 Aug 2;14(1):32
pubmed: 31375134
Int J Mol Sci. 2019 Jul 26;20(15):
pubmed: 31357514
Biochim Biophys Acta. 2006 Dec;1763(12):1755-66
pubmed: 17034877
Aging (Albany NY). 2009 Sep 14;1(9):758-61
pubmed: 20157564
Curr Pharm Des. 2016;22(26):4063-8
pubmed: 27189599
Oxid Med Cell Longev. 2017;2017:9860841
pubmed: 28811869
Am J Physiol Cell Physiol. 2016 Oct 1;311(4):C537-C543
pubmed: 27385721