biostudies-literatureLall DNIA NIH HHSHoward Hughes Medical InstituteNINDS NIH HHS2275-2291.e8https://www.ebi.ac.uk/biostudies/studies/S-EPMC8298293biostudies-literatureUnknown109(14)C9orf72 repeat expansions cause inherited amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD) and result in both loss of C9orf72 protein expression and production of potentially toxic RNA and dipeptide repeat proteins. In addition to ALS/FTD, C9orf72 repeat expansions have been reported in a broad array of neurodegenerative syndromes, including Alzheimer's disease. Here we show that C9orf72 deficiency promotes a change in the homeostatic signature in microglia and a transition to an inflammatory state characterized by an enhanced type I IFN signature. Furthermore, C9orf72-depleted microglia trigger age-dependent neuronal defects, in particular enhanced cortical synaptic pruning, leading to altered learning and memory behaviors in mice. Interestingly, C9orf72-deficient microglNeuronC9orf72 deficiency promotes microglial-mediated synaptic loss in aging and amyloid accumulation.PMC8298293R01 AG056303R01 NS085207R01 NS090934P30 AG066519RF1 AG055524R01 NS097545RF1 NS090934UE5 NS065723R25 NS065723R01 AG061895P50 AG016573R01 AG047644K08 NS105916RF1 AG047644Lall DLanderos JMota TAMahan TEShelest OBlurton-Jones MHoltzman DMUlrich JDKim JRexach JELorenzini IVazquez MBaloh RHDavtyan HO'Rourke JGSattler RBell SGhaffari LMuhammad AKMGGeschwind DHfalseC9orf72 deficiency promotes microglial-mediated synaptic loss in aging and amyloid accumulation.C9orf72 repeat expansions cause inherited amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD) and result in both loss of C9orf72 protein expression and production of potentially toxic RNA and dipeptide repeat proteins. In addition to ALS/FTD, C9orf72 repeat expansions have been reported in a broad array of neurodegenerative syndromes, including Alzheimer's disease. Here we show that C9orf72 deficiency promotes a change in the homeostatic signature in microglia and a transition to an inflammatory state characterized by an enhanced type I IFN signature. Furthermore, C9orf72-depleted microglia trigger age-dependent neuronal defects, in particular enhanced cortical synaptic pruning, leading to altered learning and memory behaviors in mice. Interestingly, C9orf72-deficient microgl2021-01-01T00:00:00Z2021 Jul2026-05-09T03:09:21.856Z2025-02-18T23:32:06.002ZS-EPMC82982933413394510.1016/j.neuron.2021.05.020