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

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

Authors :
Van Schoor E
Ospitalieri S
Moonen S
Tomé SO
Ronisz A
Ok O
Weishaupt J
Ludolph AC
Van Damme P
Van Den Bosch L
Thal DR
Source :
Acta neuropathologica [Acta Neuropathol] 2022 Sep; Vol. 144 (3), pp. 393-411. Date of Electronic Publication: 2022 Jul 22.
Publication Year :
2022

Abstract

Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of motor neurons in the motor cortex, brainstem, and spinal cord. Although ALS is considered a motor neuron disorder, neuroinflammation also plays an important role. Recent evidence in ALS disease models indicates activation of the inflammasome and subsequent initiation of pyroptosis, an inflammatory type of cell death. In this study, we determined the expression and distribution of the inflammasome and pyroptosis effector proteins in post-mortem brain and spinal cord from ALS patients (n = 25) and controls (n = 19), as well as in symptomatic and asymptomatic TDP-43 <superscript>A315T</superscript> transgenic and wild-type mice. Furthermore, we evaluated its correlation with the presence of TDP-43 pathological proteins and neuronal loss. Expression of the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome, pyroptosis effector protein cleaved Gasdermin D (GSDMD), and IL-18 was detected in microglia in human ALS 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 ALS motor cortex. Neither of this was observed in the spinal cord. Similar results were obtained in TDP-43 <superscript>A315T</superscript> mice, where microglial pyroptosis activation was significantly increased in the motor cortex upon symptom onset, and correlated with neuronal loss. There was no significant correlation with the presence of TDP-43 pathological proteins both in human and mouse tissue. Our findings emphasize the importance of microglial NLRP3 inflammasome-mediated pyroptosis activation for neuronal degeneration in ALS and pave the way for new therapeutic strategies counteracting motor neuron degeneration in ALS by inhibiting microglial inflammasome/pyroptosis activation.<br /> (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Details

Language :
English
ISSN :
1432-0533
Volume :
144
Issue :
3
Database :
MEDLINE
Journal :
Acta neuropathologica
Publication Type :
Academic Journal
Accession number :
35867112
Full Text :
https://doi.org/10.1007/s00401-022-02466-9