NF-E2-related factor 2 activation boosts antioxidant defenses and ameliorates inflammatory and amyloid properties in human Presenilin-1 mutated Alzheimer's disease astrocytes.
Alzheimer Disease
/ metabolism
Amyloid beta-Peptides
/ metabolism
Amyloidogenic Proteins
/ metabolism
Animals
Antioxidants
/ pharmacology
Astrocytes
/ drug effects
Disease Models, Animal
Humans
Inflammation
/ metabolism
NF-E2-Related Factor 2
/ metabolism
Plaque, Amyloid
/ metabolism
Presenilin-1
/ metabolism
Alzheimer's disease
NRF2
astrocytes
inflammation
oxidative stress
Journal
Glia
ISSN: 1098-1136
Titre abrégé: Glia
Pays: United States
ID NLM: 8806785
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
received:
05
07
2019
revised:
11
10
2019
accepted:
11
10
2019
pubmed:
2
11
2019
medline:
20
11
2020
entrez:
1
11
2019
Statut:
ppublish
Résumé
Alzheimer's disease (AD) is a common dementia affecting a vast number of individuals and significantly impairing quality of life. Despite extensive research in animal models and numerous promising treatment trials, there is still no curative treatment for AD. Astrocytes, the most common cell type of the central nervous system, have been shown to play a role in the major AD pathologies, including accumulation of amyloid plaques, neuroinflammation, and oxidative stress. Here, we show that inflammatory stimulation leads to metabolic activation of human astrocytes and reduces amyloid secretion. On the other hand, the activation of oxidative metabolism leads to increased reactive oxygen species production especially in AD astrocytes. While healthy astrocytes increase glutathione (GSH) release to protect the cells, Presenilin-1-mutated AD patient astrocytes do not. Thus, chronic inflammation is likely to induce oxidative damage in AD astrocytes. Activation of NRF2, the major regulator of cellular antioxidant defenses, encoded by the NFE2L2 gene, poses several beneficial effects on AD astrocytes. We report here that the activation of NRF2 pathway reduces amyloid secretion, normalizes cytokine release, and increases GSH secretion in AD astrocytes. NRF2 induction also activates the metabolism of astrocytes and increases the utilization of glycolysis. Taken together, targeting NRF2 in astrocytes could be a potent therapeutic strategy in AD.
Identifiants
pubmed: 31670864
doi: 10.1002/glia.23741
pmc: PMC7003860
doi:
Substances chimiques
Amyloid beta-Peptides
0
Amyloidogenic Proteins
0
Antioxidants
0
NF-E2-Related Factor 2
0
NFE2L2 protein, human
0
Presenilin-1
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
589-599Informations de copyright
© 2019 The Authors. Glia published by Wiley Periodicals, Inc.
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