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

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 () and Kevin Talbot ()
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Björn F. Vahsen: University of Oxford, John Radcliffe Hospital
Sumedha Nalluru: University of Oxford, John Radcliffe Hospital
Georgia R. Morgan: University of Oxford, John Radcliffe Hospital
Lucy Farrimond: University of Oxford, John Radcliffe Hospital
Emily Carroll: University of Oxford, John Radcliffe Hospital
Yinyan Xu: University of Oxford, John Radcliffe Hospital
Kaitlyn M. L. Cramb: University of Oxford, Dorothy Crowfoot Hodgkin Building
Benazir Amein: University of Oxford, John Radcliffe Hospital
Jakub Scaber: University of Oxford, John Radcliffe Hospital
Antigoni Katsikoudi: University of Oxford, Dorothy Crowfoot Hodgkin Building
Ana Candalija: University of Oxford, John Radcliffe Hospital
Mireia Carcolé: UK Dementia Research Institute at UCL and Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology
Ruxandra Dafinca: University of Oxford, John Radcliffe Hospital
Adrian M. Isaacs: UK Dementia Research Institute at UCL and Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology
Richard Wade-Martins: University of Oxford, Dorothy Crowfoot Hodgkin Building
Elizabeth Gray: University of Oxford, John Radcliffe Hospital
Martin R. Turner: University of Oxford, John Radcliffe Hospital
Sally A. Cowley: University of Oxford
Kevin Talbot: University of Oxford, John Radcliffe Hospital

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41603-0

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