FABP7 upregulation induces a neurotoxic phenotype in astrocytes

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.

Beyond the GFAP-Astrocyte Protein Markers in the Brain

“…FABP7, also known as brain lipid-binding protein (BLBP), is a transporter expressed by injured astrocytes and a marker of Bergmann glia and radial glia [ 132 , 133 ]. In astrocytes from the spinal cord it induces a pro-inflammatory phenotype that renders these cells toxic to motor neurons in coculture [ 134 ].…”

Metabolic Enzyme Alterations and Astrocyte Dysfunction in a Murine Model of Alexander Disease With Severe Reactive Gliosis

“…Subsequently, Fabp7 was selected for additional analysis by PRM-MS and immunohistochemistry because deletion of the Fabp7 gene in mice results in reduced proliferation of reactive astrocytes following cortical stab injuries ( 40 ), which shares some clinical features to AxD including a reactive gliosis phenotype with upregulation of Gfap. An additional rationale for investigating Fabp7 was based on a recent report demonstrating that Fabp7 is upregulated in a mutant human superoxide dismutase 1 (hSOD1) mouse model of ALS and causes an NF-κB-driven inflammatory response that is damaging for motor neuron survival ( 78 ). In the context of AxD, NF-κB may serve to increase Gfap to toxic levels, since NF-κB (Rela) was significantly upregulated in the untargeted proteomics dataset by 2.1-fold in GFAP Tg ; Gfap +/ R236H mice, and its blockade by aspirin has been shown to lower Gfap levels in astrocytes ( 79 ).…”

“…Among the various PPAR isoforms, the strongest relationship observed in the untargeted μDIA proteomic dataset implicates the activation of PPARα in GFAP Tg ; Gfap +/ R236H mice due to the heightened amounts of its corresponding transcriptional target proteins (Acot1, Acsl3, Hmgcs2, Acox1) ( 43 , 44 , 45 ), although it should be noted that the prior studies used to implicate the expression of these particular PPAR target genes were generated from nonbrain tissues and some downstream targets of the pathway are expressed by multiple PPAR isoforms ( 47 , 48 ). Altogether, the upregulation of Fabp7 in GFAP Tg ; Gfap +/ R236H mice and FABP7 in AxD patients is expected to induce a harmful phenotype by generating an NF-κB inflammatory response ( 78 ) resulting in heightened levels of Gfap ( 79 ) and decreasing the anti-inflammatory effects of the PPAR pathway ( 80 , 81 ).…”

Fatty Acid-Binding Proteins Aggravate Cerebral Ischemia-Reperfusion Injury in Mice

“…Astrocytes expressing FABP7 are crucial for the normal development of dendritic arbors, the formation of and transmission through the excitatory synapses of cortical neurons [ 40 ], and even increases the loss of ventral horn neurons in FABP7-knockout mice with spinal cord injury [ 41 ]. Conversely, FABP7 overexpression can directly promote a nuclear factor-kappa B (NF-κB)-driven pro-inflammatory response in astrocytes of mice with amyotrophic lateral sclerosis and can ultimately reduce motor neuron survival [ 42 ], whereas FABP7 knockdown in the developing brain can increase the proportion of neurons [ 43 , 44 ]. Based on these findings, we hypothesized that FABPs elicit detrimental effects on mitochondrial homeostasis and neuroinflammation, whereas FABP7 is partially required for neuronal differentiation in the developmental stages.…”