Defining the Microglia Response during the Time Course of Chronic Neurodegeneration

Abstract

Inflammation has been proposed as a major component of neurodegenerative diseases, although the precise role it plays has yet to be defined. We 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 upregulated during disease, regardless of the strain of mouse or prion protein, are expressed predominantly 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/cJFms-EGFP/− mice, which express enhanced green fluorescent protein under the 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 proinflammatory signature in addition to an upregulation 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 upregulated throughout the disease process are expressed predominantly by microglia. A disease-specific, highly proinflammatory signature was observed in addition to an upregulation 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.

A core transcriptional signature of human microglia: Derivation and utility in describing region‐dependent alterations associated with Alzheimer's disease

“…These analyses have been crucial in expanding our knowledge of their functional biology, however, our preliminary analysis found there to be limited inter‐study agreement across the published microglia gene signatures. Such inconsistency may have arisen due to technical differences in tissue sampling, brain areas analyzed, differences in patient characteristics and biological variance, including the regional‐heterogeneity of microglia in the CNS (Grabert et al, ; Lai, Dhami, Dibal, & Todd, ; Lawson et al, ; Vincenti et al, ; Yokokura et al, ). This highlighted a need to derive a refined human microglial signature that would enable a more precise characterization of these cells in the healthy and diseased human brain.…”

Microglia in prion diseases

“…This study revealed that the genes upregulated after prion infection, regardless of the prion strain or mouse genetic background, are expressed predominantly by activated microglia (39), contributing to a growing recognition of the importance of microglia in prion pathogenesis. Analysis of microglia isolated from prion-infected mice demonstrated that, in addition to an upregulation of genes associated with metabolic and respiratory stress, a disease-specific, highly proinflammatory profile was observed (39).…”

“…This study revealed that the genes upregulated after prion infection, regardless of the prion strain or mouse genetic background, are expressed predominantly by activated microglia (39), contributing to a growing recognition of the importance of microglia in prion pathogenesis. Analysis of microglia isolated from prion-infected mice demonstrated that, in addition to an upregulation of genes associated with metabolic and respiratory stress, a disease-specific, highly proinflammatory profile was observed (39). Another transcriptomic analysis of various brain regions in the presence or absence of neurodegeneration revealed that there are at least two distinct microglial responses in prion-infected brains: a homeostatic response across all brain regions and an innate immune response restricted to sites of neurodegeneration (40).…”

Role of polysaccharide and lipid in lipopolysaccharide induced prion protein conversion

“…However, moderate repeated doses of LPS have been shown to cause systemic inflammation, which accelerates features of neurodegenerative disease in combination with existing disease pathology 23 . Furthermore, there is a strong link between a highly pro-inflammatory response in microglia and prion disease progression 24 . Intriguingly treatment of the mucosal side of colon tissue with LPS caused up-regulation of genes related to TLR and the inflammasome 25 .…”