Introduction Prion diseases are transmissible, neurodegenerative disorders to which there are no cures. Previous studies show that treatments that lead to the depletion of microglia accelerate prion disease and increases the accumulation of prions in the brain, suggesting that microglia provide neuroprotection by phagocytosing and destroying prions. In Csf1rΔFIRE mice, the deletion of an enhancer within the colony stimulating factor 1 receptor (Csf1r) gene specifically blocks microglia development, however, their brains develop normally with none of the deficits reported in other microglia-deficient models. Methods Csf1rΔFIRE mice were used as a refined model to study the impact of complete microglia-deficiency on central nervous system prion disease. Mice were challenged intracerebrally with ME7 mouse adapted scrapie prions and monitored for progression of prion disease by weekly clinical assessment and CatWalk automated gait analysis. Mice were sacrificed at defined humane clinical endpoints (terminal) and a group sacrificed at 98 days post infection to monitor rate of prion neuropathogenesis. Brains were assessed by neuropathological analysis including immunohistochemistry, Western blot, real-time quaking induced conversion (RT-QuIC), and reverse transcriptase quantitative polymerase chain reaction (RT-qPCR). Approach for statistical analysis Mice were grouped according to confirmed genotype and prion-challenge status. Survival curve analysis performed by Log-rank [Mantel Cox] Test. Image and gene expression analyses performed by Student’s t-test or ANOVA. CatWalkXT analysis performed using two-way ANOVA. Values of P < 0.05 were accepted as significant. Results Csf1rΔFIRE mice succumbed to prion disease much earlier than wild-type mice as determined by both clinical assessment and gait analyses. This was not due to increased accumulation of prions in their brains. Instead, astrocytes displayed earlier, non-polarized reactive activation with enhanced synaptic pruning and unfolded protein responses. In conclusion, our data indicate that the microglia are not required for prion disease and provide neuroprotection independently of prion clearance by inhibiting neurotoxic reactive astrocyte activation.
|Publication status||Published - 12 Apr 2021|
|Event||British Neuroscience Association 2021 : Festival of Neuroscience - Virtual|
Duration: 12 Apr 2021 → 15 Apr 2021
|Conference||British Neuroscience Association 2021|
|Period||12/04/21 → 15/04/21|