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NF-E2-related factor 2 activation boosts antioxidant defenses and ameliorates inflammatory and amyloid properties in human Presenilin-1 mutated Alzheimer's disease astrocytes

Oksanen, Minna ; Hyötyläinen, Ida ; Trontti, Kalevi ; Rolova, Taisia ; Wojciechowski, Sara ; Koskuvi, Marja ; Viitanen, Matti ; Levonen, Anna Liisa ; Hovatta, Iiris and Roybon, Laurent LU , et al. (2020) In GLIA 68(3). p.589-599
Abstract

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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Alzheimer's disease, astrocytes, inflammation, NRF2, oxidative stress
in
GLIA
volume
68
issue
3
pages
11 pages
publisher
John Wiley & Sons Inc.
external identifiers
  • scopus:85074854580
  • pmid:31670864
ISSN
0894-1491
DOI
10.1002/glia.23741
language
English
LU publication?
yes
id
a056c103-d1e5-45d8-a8ee-4874d0664420
date added to LUP
2019-12-06 16:53:57
date last changed
2024-05-15 02:23:05
@article{a056c103-d1e5-45d8-a8ee-4874d0664420,
  abstract     = {{<p>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.</p>}},
  author       = {{Oksanen, Minna and Hyötyläinen, Ida and Trontti, Kalevi and Rolova, Taisia and Wojciechowski, Sara and Koskuvi, Marja and Viitanen, Matti and Levonen, Anna Liisa and Hovatta, Iiris and Roybon, Laurent and Lehtonen, Šárka and Kanninen, Katja M. and Hämäläinen, Riikka H. and Koistinaho, Jari}},
  issn         = {{0894-1491}},
  keywords     = {{Alzheimer's disease; astrocytes; inflammation; NRF2; oxidative stress}},
  language     = {{eng}},
  number       = {{3}},
  pages        = {{589--599}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{GLIA}},
  title        = {{NF-E2-related factor 2 activation boosts antioxidant defenses and ameliorates inflammatory and amyloid properties in human Presenilin-1 mutated Alzheimer's disease astrocytes}},
  url          = {{http://dx.doi.org/10.1002/glia.23741}},
  doi          = {{10.1002/glia.23741}},
  volume       = {{68}},
  year         = {{2020}},
}