# Lactate Dehydrogenase Inhibition Reverts the Fatty Acid‐Induced Neurotoxic Phenotype of Astrocytes

## TL;DR

This study shows that inhibiting lactate dehydrogenase can reverse fatty acid-induced harmful changes in astrocytes linked to ALS.

## Contribution

The novel finding is that lactate dehydrogenase inhibition reverses lipid droplet accumulation and neurotoxicity in ALS astrocytes.

## Key findings

- ALS models show increased lipid droplet accumulation in astrocytes.
- Lipid droplet accumulation correlates with a proinflammatory, neurotoxic astrocyte phenotype.
- Pharmacological or genetic inhibition of lactate dehydrogenase reduces lipid droplet accumulation in ALS astrocytes.

## Abstract

Astrocytes are central to lipid metabolism in the central nervous system. Due to their morphological and functional characteristics, astrocytes can uptake fatty acids (FAs) from the bloodstream and extracellular space and store them in lipid droplets (LD). LD are dynamic organelles, whose accumulation in astrocytes has been shown to occur upon exposure to various stress stimuli. Different hypotheses proposed to explain motor neuron degeneration in amyotrophic lateral sclerosis (ALS) implicate mitochondrial dysfunction and oxidative stress. Mitochondrial dysfunction in astrocytes is associated with elevation of cytoplasmic lipids and lipid‐binding proteins. We observed increased LD in the spinal cord of symptomatic ALS mice, as well as in human transdifferentiated astrocytes obtained from ALS patients. Using a co‐culture model, we examined the effect of FA overload and its impact on astrocyte–motor neuron interaction. LD accumulation was tightly coupled with an NF‐κB‐driven proinflammatory response in nontransgenic astrocytes, correlating with motor neuron toxicity. These results provide additional evidence to the notion that altered energy balance may contribute to neuronal death in ALS. Furthermore, pharmacological inhibition of lactate dehydrogenase (LDH) reversed LD accumulation in mouse and human astrocytes expressing ALS‐linked mutations. Genetic ablation of LDHA similarly reduced LD accumulation in response to FA treatment. Collectively, our data underscore the role of lipid metabolism in astrocyte–neuron interactions in ALS models and suggest that LD accumulation, rather than serving solely as a protective mechanism, reflects a metabolic stress state linked to a detrimental phenotypic transformation in astrocytes.

ALS models display increased LD accumulation.LD accumulation is linked to a neurotoxic phenotype in astrocytes.Lactate dehydrogenase inhibition reverts LD accumulation in ALS astrocytes.

ALS models display increased LD accumulation.

LD accumulation is linked to a neurotoxic phenotype in astrocytes.

Lactate dehydrogenase inhibition reverts LD accumulation in ALS astrocytes.