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  • C9orf72-ALS human iPSC microglia are pro-inflammatory and toxic to co-cultured motor neurons via MMP9.

C9orf72-ALS human iPSC microglia are pro-inflammatory and toxic to co-cultured motor neurons via MMP9.

Nature communications (2023-09-22)
Björn F Vahsen, Sumedha Nalluru, Georgia R Morgan, Lucy Farrimond, Emily Carroll, Yinyan Xu, Kaitlyn M L Cramb, Benazir Amein, Jakub Scaber, Antigoni Katsikoudi, Ana Candalija, Mireia Carcolé, Ruxandra Dafinca, Adrian M Isaacs, Richard Wade-Martins, Elizabeth Gray, Martin R Turner, Sally A Cowley, Kevin Talbot
ABSTRACT

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, with additional pathophysiological involvement of non-neuronal cells such as microglia. The commonest ALS-associated genetic variant is a hexanucleotide repeat expansion (HRE) mutation in C9orf72. Here, we study its consequences for microglial function using human iPSC-derived microglia. By RNA-sequencing, we identify enrichment of pathways associated with immune cell activation and cyto-/chemokines in C9orf72 HRE mutant microglia versus healthy controls, most prominently after LPS priming. Specifically, LPS-primed C9orf72 HRE mutant microglia show consistently increased expression and release of matrix metalloproteinase-9 (MMP9). LPS-primed C9orf72 HRE mutant microglia are toxic to co-cultured healthy motor neurons, which is ameliorated by concomitant application of an MMP9 inhibitor. Finally, we identify release of dipeptidyl peptidase-4 (DPP4) as a marker for MMP9-dependent microglial dysregulation in co-culture. These results demonstrate cellular dysfunction of C9orf72 HRE mutant microglia, and a non-cell-autonomous role in driving C9orf72-ALS pathophysiology in motor neurons through MMP9 signaling.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Cytochalasin D, Ready Made Solution, from Zygosporium mansonii, 5 mg/mL in DMSO
Sigma-Aldrich
Decamethylcyclopentasiloxane, 97%