Temporary deterioration of health and behavior during pexidartinib-mediated microglia depletion and repopulation in progranulin-deficient mice

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Abstract
Progranulin (PGRN) is a neurotrophic and anti-inflammatory factor produced mainly by neurons and microglia in the central nervous system. Progranulin haploinsufficiency causes frontotemporal dementia (FTD). In a previous study we showed that transgenic restoration of progranulin in neurons in progranulin knockout mice (NestinGrn KOBG k nock o ut b ack g round) did not prevent the dementia-like phenotype. Here, we assessed if pharmacologic microglia depletion via PLX3397-diet (CSF1R-antagonist) had therapeutic value in these mice. Microglia depletion and spontaneous repopulation was confirmed in immunofluorescence and rtPCR studies. There was no difference in depletion or repopulation efficiency between NesGrn KOBG, PGRN KO and heterozygous (het) PGRN mice, but microglia repopulated faster than in control Grn-flfl mice, and the morphology of primary PGRN deficient microglia during repopulation was closer to homeostatic microglia, and it was accompanied by a remarkable restoration of dendritic spines and synaptic structures. Regardless of these positive effects, NesGrn KOBG and PGRN het mice experienced serious side effects during microglia depletion which peaked around the microglia nadir. Overactivity and excessive grooming escalated and caused serious skin lesions. Bulk transcriptomic and metabolomic studies in the brain taken 8 weeks after the end of PLX-diet clearly revealed differences between genotypes but mostly no lasting impact of PLX-diet, except for a further increase of proinflammatory genes, cathepsins and complement factors in PLX-treated groups. Cell type specific lipidomic studies revealed a time dependent switch not only in microglia but also astrocytes upon PLX3397 treatment. While nadir-microglia were triglyceride-laden, repopulated microglia returned to normal TG levels but were enriched in ether-bound phosphatidylcholines (PC-O) and lysophosphatidylglycerol species which are pro-inflammatory lipids; and astrocytes overtook the TG burden during repopulation. Our data suggest that microglia depletion may cause a deterioration in progranulin-deficiency.

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