Defining the microglia response during the time course of chronic neurodegeneration

Inflammation has been proposed as a major component of neurodegenerative diseases although the precise role it plays has yet to be defined. We have examined the role of key contributors to this inflammatory process, microglia, the major resident immune cell population of the brain, in a prion disease model of chronic neurodegeneration. Initially, we performed an extensive reanalysis of a large study of prion disease, where the transcriptome of mouse brains had been monitored throughout the time-course of disease. Our analysis has provided a detailed classification of the disease-associated genes based on cell type of origin and gene function. This revealed that the genes up-regulated during disease, regardless of the strain of mouse or prion protein, are expressed predominately by activated microglia. In order to study the microglia contribution more specifically we established a mouse model of prion disease in which the 79A murine prion strain was introduced by an intraperitoneal route into BALB/cJ(Fms-EGFP/-) mice, which express Enhanced Green Fluorescent Protein (EGFP) under control of the c-fms operon. Samples were taken at time points during disease progression and histological analysis of the brain and transcriptional analysis of isolated microglia was carried out. The analysis of isolated microglia revealed a disease specific, highly pro-inflammatory signature in addition to an up-regulation of genes associated with metabolism and respiratory stress. This study strongly supports the growing recognition of the importance of microglia within the prion disease process and identifies the nature of the response through gene expression analysis of isolated microglia.

IMPORTANCE: Inflammation has been proposed as a major component of neurodegenerative diseases. We have examined the role of key contributors to this inflammatory process, microglia, the major resident immune cell population of the brain, in a murine prion disease model of chronic neurodegeneration. Our study demonstrates that genes up-regulated throughout the disease process, are expressed predominately by microglia. A disease specific highly pro-inflammatory signature was observed in addition to an up-regulation of genes associated with metabolism and respiratory stress. This study strongly supports the growing recognition of the important contribution of microglia to a chronic neurodegenerative disease process.