FABP7 upregulation induces a neurotoxic phenotype in astrocytes.
Glia
; 68(12): 2693-2704, 2020 12.
Article
em En
| MEDLINE
| ID: mdl-32619303
ABSTRACT
Fatty acid binding proteins (FABPs) are key regulators of lipid metabolism, energy homeostasis, and inflammation. They participate in fatty acid metabolism by regulating their uptake, transport, and availability of ligands to nuclear receptors. In the adult brain, FABP7 is especially abundant in astrocytes that are rich in cytoplasmic granules originated from damaged mitochondria. Mitochondrial dysfunction and oxidative stress have been implicated in the neurodegenerative process observed in amyotrophic lateral sclerosis (ALS), either as a primary cause or as a secondary component of the pathogenic process. Here we investigated the expression of FABP7 in animal models of human superoxide dismutase 1 (hSOD1)-linked ALS. In the spinal cord of symptomatic mutant hSOD1-expressing mice, FABP7 is upregulated in gray matter astrocytes. Using a coculture model, we examined the effect of increased FABP7 expression in astrocyte-motor neuron interaction. Our data show that FABP7 overexpression directly promotes an NF-κB-driven pro-inflammatory response in nontransgenic astrocytes that ultimately is detrimental for motor neuron survival. Addition of trophic factors, capable of supporting motor neuron survival in pure cultures, did not prevent motor neuron loss in cocultures with FABP7 overexpressing astrocytes. In addition, astrocyte cultures obtained from symptomatic hSOD1-expressing mice display upregulated FABP7 expression. Silencing endogenous FABP7 in these cultures decreases the expression of inflammatory markers and their toxicity toward cocultured motor neurons. Our results identify a key role of FABP7 in the regulation of the inflammatory response in astrocytes and identify FABP7 as a potential therapeutic target to prevent astrocyte-mediated motor neuron toxicity in ALS.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Astrócitos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Glia
Assunto da revista:
NEUROLOGIA
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Estados Unidos