Effect of microglial depletion on neurodegeneration in a multiple sclerosis model

ANABELLA A. DI PIETRO; LAURA A PASQUINI

Congreso; American Society for Neurochemistry (ASN) 2021 Virtual Meeting; 2021

Disability in patients with multiple sclerosis (MS) resultsfrom neu-ronal and axonal loss. Prolonged cuprizone(CPZ) intoxication is widely used as a MS model becauseit triggers chronic demyelination, neurodegeneration, astrogliosisand microgliosis. Exacerbated microglia (MG) activationis associated with impaired remyelination andneurodegeneration. As MG are physiologically dependenton colony-stimulating factor 1 receptor (CSF-1R) signaling,MG can be almost completely eliminated from the brainusing CSF-1R inhibitors. Therefore, the present workaimed to evaluate the effects of CSF-1R inhibitor BLZ945on myelin status, neurodegeneration and astrogliosis duringchronic CPZ demyelination. Mice were fed either control orCPZ chow for 12 weeks and orally gavaged vehicle orBLZ945 from the 2nd week of CPZ treatment. BLZ945induced a reduction in the microglial population in all structuresevaluated. Astrogliosis was attenuated only in the cortex(CX), cerebellum (CB) and forceps major of the corpuscallosum (fmjCC). A recovery in myelin basic protein (MBP)and Sudan black (SB) staining showed BLZ945 to protectmyelin. The percentage of MBP-positive area increased inCX and throughout the CC, while SB intensity increasedin the CB, fmjCC, anterior corpus callosum (aCC), fimbriaof the hippocampus (FI) and striatum (ST). However, positiveamino-cupric-silver staining was more prominent inaxons traversing the ST and fibers throughout the CCwith BLZ945 treatment. Axonal degeneration was accompaniedby terminal axonal ovoids character-istic of inflammatorydemyelination. These results indicate thatneurodegeneration does not exclusively result from demyelinationand that MG depletion could prevent demyelinationbut also exacerbate axonal degeneration.