Glial Cells in Brain Work as Toxic Agents in ALS, Study Reports

Astroglial cells in the brain were seen to contribute to the death of neurons by promoting inflammation in an in vitro laboratory model of sporadic amyotrophic lateral sclerosis (ALS).

Astrocytes are brain cells that are usually known for their protective role toward neurons in conditions such as stroke and spinal cord injury. But they also can exert a negative effect in the presence of certain factors released by microglia, inflammation mediators in the brain. The precise role of astroglia in the pathophysiology of ALS is still not fully understood.

The study, “Astroglia acquires a toxic neuroinflammatory role in response to the cerebrospinal fluid from amyotrophic lateral sclerosis patients,” was published by Pooja-Shree Mishra and colleagues in the Journal of Inflammation.

To determine what role astrocytes played in ALS inflammation, the researchers used rat astroglial cultures, which they exposed to cerebrospinal fluid (CSF) from six drug-naive ALS patients and six age-matched neurological patients serving as controls. Their objective was to check whether the presence of the ALS in the fluid (ALS-CSF) would induce changes in the levels of several pro-inflammatory and anti-inflammatory markers, such as the cytokines COX-2 and PGE-2, trophic factors, glutamate, nitric oxide (NO), and reactive oxygen species (ROS). [Cytokines are a group of proteins, produced by the immune system, that act as chemical messages to other cells and can affect their behavior.]

Researchers observed that the ALS cerebrospinal fluid increased the production and release of inflammatory factors, including cytokines IL-6, TNF-α, COX-2 and PGE-2, and decreased that of anti-inflammatory factors, such as cytokine IL-10 and the beneficial trophic factors VEGF and GDNF. Moreover, increased levels of glutamate, NO, and ROS — markers of toxicity — were found in the cells in response to ALS-CSF.

To support these observations, researchers next extracted the medium of these astroglial cultures and put it into contact with motor neurons in culture (NSC-34 cell line).  They observed that the medium, containing all the secretions of the astroglial cells in response to ALS-CSF, caused motor neurons to degenerate. This observation led the team to conclude that ALS pathology is propagated through the circulating fluid (ALS-CSF) to astroglial cells, triggering neuronal damage and death.

“(…) the [increase] of pro-inflammatory cytokines and [decrease] of anti-inflammatory cytokine suggest a clear ALS-CSF-induced astroglial cytokine imbalance,” the authors wrote. “Based on our results, we would like to advocate the need for combinatorial therapies to combat the multidimensional glial pathology and its compounding effect on the degeneration of motor neurons.”