Increased pyroptosis activation in white matter microglia is associated with neuronal loss in ALS motor cortex.

- Posted by

Although Amyotrophic Lateral Sclerosis is considered a motor neuron disorder, neuroinflammation also plays an important role. How a cell dies is critical, as it can drive local immune activation and tissue damage. Classical apoptosis engages several mechanisms to evoke "immunologically silent" responses, whereas other forms of programmed death such as pyroptosis, necroptosis, and ferroptosis release molecules that can potentiate immune responses and inflammation. enter image description here In this new study, the authors Evelien Van Schoor, Dietmar Rudolf Thal and colleagues (including Albert C Ludolph) of Ulm and Leuven universities, determined the expression and distribution of the inflammasome and pyroptosis effector proteins in post-mortem brain and spinal cord from Amyotrophic Lateral Sclerosis patients and controls, as well as in symptomatic and asymptomatic TDP-43 transgenic and wild-type mice.

The authors evaluated its correlation with the presence of TDP-43 pathological proteins and neuronal loss. Expression of pyroptosis effector protein cleaved Gasdermin D (GSDMD), and IL-18 was detected in microglia in human Amyotrophic Lateral Sclerosis motor cortex and spinal cord, indicative of canonical inflammasome-triggered pyroptosis activation.

The number of cleaved GSDMD-positive precentral white matter microglia was increased compared to controls and correlated with a decreased neuronal density in human Amyotrophic Lateral Sclerosis motor cortex. Neither of this was observed in the spinal cord.

Similar results were obtained in TDP-43 mice model, where microglial pyroptosis activation was significantly increased in the motor cortex upon symptom onset, and correlated with neuronal loss. yet there was no significant correlation with the presence of TDP-43 pathological proteins both in human and mouse tissue.

The authors' findings emphasize the importance of microglial NLRP3 inflammasome-mediated pyroptosis activation for neuronal degeneration in Amyotrophic Lateral Sclerosis and pave the way for new therapeutic strategies counteracting motor neuron degeneration in Amyotrophic Lateral Sclerosis by inhibiting microglial inflammasome/pyroptosis activation.

As a commentary on this article, we can observe there are some rationales for testing the efficacy of fumarates in ALS models. Dimethyl fumarate (DMF) is an ester of fumaric acid, which can be isolated from the plant Fumaria officinalis. In folk medicine, the herb has been used for skin diseases, rheumatism, arteriosclerosis, constipation and cystitis. In Germany it was licensed under the brand name Fumaderm and is still used today.

DMF ameliorated LPS and ATP-induced NLRP3 inflammasome activation by reducing IL-1β, IL-18, caspase-1, and NLRP3 levels, reactive oxygen species formation and damage, and inhibiting pyroptotic cell death in N9 murine microglia via Nrf2/NF-κB pathways. DMF also improved LPS-induced sickness behavior in male mice and decreased caspase-1/NLRP3 levels via Nrf2 activation. Contact the author of this post

Read the original article on Pubmed

Please, help us continue to provide valuable information: