ALS/FTD-linked TBK1 deficiency in microglia induces an aged-like microglial signature and drives social recognition deficits. [in vitro_Microglia]

TANK-Binding Kinase 1 (TBK1) is involved in autophagy and immune signaling. Dominant loss-of-function mutations in TBK1 are linked to Amyotrophic Lateral Sclerosis (ALS), Fronto-temporal dementia (FTD) and ALS/FTD. However, pathogenic mechanisms remain unclear, particularly the cell-type specific disease contributions of TBK1 mutations. Here, we focus on cell-specific Tbk1 deletion in motor neurons or microglia. We find that deleting Tbk1 from mouse motor neurons does not induce transcriptional stress, despite lifelong signs of autophagy deregulations. Conversely, Tbk1 deletion in microglia alters their homeostasis and reactive responses. In both spinal cord and brain, Tbk1 deletion leads to a pro-inflammatory, primed microglial signature with features of ageing and neurodegeneration. While it does not induce or modify ALS-like motor neuron damage, microglial Tbk1 deletion causes early FTD-like social recognition deficits. This phenotype is linked to focal microglial activation and T cell infiltration in the substantia nigra pars reticulata and pallidum. Our results reveal that part of TBK1-linked FTD disease originates from microglial dysfunction. Overall design: Microglial cells primary cultures from P0/P1 mouse pups. Mice had a deletion of Tbk1 in microglial cells specifically of respectively 0 Tbk1 allele (WT), 1 Tbk1 allele (HET), 2 Tbk1 alleles (KO). Tbk1fl/fl, Cx3CR1-Cre- mice = WT; Tbk1fl/+, Cx3CR1-Cre+ = HET; Tbk1fl/fl, Cx3CR1-Cre+ = KO. Microglial cultures were unstimulated (untreated, UT), treated with lipopolysaccharide (LPS) or interleukin-4 (IL4) or poly(I:C) for 24h. Biological replicates were 5 independant cultures.