MIcroglial early Neuroinflamatory Dysfunction in Fontotemporal Dementia and Amyotrophic Lateral Sclerosis due to C9orf72 repeat Expansions – MIND FACE

Expansion of a (G4C2) repeat in C9orf72 is the most common autosomal dominant cause of frontotemporal dementia and amyotrophic lateral
sclerosis (ALS). Strong arguments indicate that immune-system related dysfunction may contribute as disease modifier to the large phenotypic
variation in onset age, clinical presentation and disease progression in C9orf72ex. Novel tools now enable us to dissect the role of immune-related
dysfunction in detail. Single-nucleus RNA sequencing (snRNAseq) of microglia in C9orf72exp brains from the Netherlands Brain Bank will allow us to
reveal microglial-related biological pathways involved in the pathophysiology of C9orf72. Based on the high expression of C9orf72 protein, abundant
RNA-foci and dipeptide repeats (DPR) in peripheral blood monocytic cells (PBMCs) from C9orf72exp patients, we will investigate the use of specific
and sensitive assays as readouts for disease onset, severity and progression, and correlate these to other fluid neuroinflammation biomarkers. As
changes on 7T MR imaging and MR spectroscopy can be sensitive to neuroinflammatory processes, we will investigate the dynamic process of
neuroinflammation during the disease course in C9orf72 pre- and symptomatic carriers over time, and correlate MRI and MRS findings with fluid
biomarkers and RNA foci in PBMCs. With mixed cultures derived from iPS cells and 3D multimodal co-culture models in human forebrain organoids
(hFO) seeded with monocyte-derived microglia-like cells (MDMIs) directly derived from C9ORF72exp carriers, we aim to test the identified biological
pathways from the snRNAseq data of C9orf72exp brains. Integrating generated data from snRNAseq of C9orf72exp brains, microglial activation on
7TMRI/MRS, neuroinflammatory proteins in human fluids, and neuron-microglial interactions in iPS cell and organoid models may provide immunerelated
biomarkers and targets to modify the disease activity in C9orf72exp.