Regulation of Microglial Proliferation during Chronic Neurodegeneration

Abstract

An important component of chronic neurodegenerative diseases is the generation of an innate inflammatory response within the CNS.Microglial and astroglial cells play a key role in the development and maintenance of this inflammatory response, showing enhanced proliferation and activation. We studied the time course and regulation of microglial proliferation, using a mouse model of prion disease. Our results show that the proliferation of resident microglial cells accounts for the expansion of the population during the development of the disease. We identify the pathway regulated by the activation of CSF1R and the transcription factors PU.1 and C/EBP␣ as the molecular regulators of the proliferative response, correlating with the chronic human neurodegenerative conditions variant CreutzfeldtJakob disease and Alzheimer's disease. We show that targeting the activity of CSF1R inhibits microglial proliferation and slows neuronal damage and disease progression. Our results demonstrate that microglial proliferation is a major component in the evolution of chronic neurodegeneration, with direct implications for understanding the contribution of the CNS innate immune response to disease progression.

Microglia in prion diseases

“…In addition, there was decreased expression of proinflammatory cytokines (IL-6 and IL-1β) and increased expression of antiinflammatory cytokines (ARG1 and YM1). Blocking of CSF1R by GW2580 also improved behavioral performance and prolonged survival of prion-infected mice (44). Therefore, manipulation of microglial activation to a beneficial phenotype represents a potential therapeutic approach for prion disease.…”

“…that the neuronal damage was attenuated and prion progression was delayed upon treatment with CSF1 receptor (CSF1R) inhibitor to arrest microglial proliferation, suggesting a detrimental role of microglial proliferation in prion diseases (44).…”

Microglia in Alzheimer’s disease

“…Little is known about microglial proliferative responses in the brain. Increased microglial proliferation has been described in the brains of AD patients (135), and in the prodromal stage of Parkinson disease (136), suggesting that microglial proliferation is an early event in the course of neurodegenerative diseases. Increased microglial proliferation was observed in several murine AD models (63), appearing with plaque onset and persisting for 18 months (63).…”

Enhanced microglial pro‐inflammatory response to lipopolysaccharide correlates with brain infiltration and blood–brain barrier dysregulation in a mouse model of telomere shortening

“…Indeed, microglia telomere shortening has been associated with increasing age and dementia (Flanary et al ., 2007). The proliferative capacity of microglia has shown to be linked to its innate immune response (Shankaran et al ., 2007) and seems to be a critical component in the evolution of chronic neurodegeneration (Gomez‐Nicola et al ., 2013). In this study, we investigated whether telomere shortening could potentially alter the inflammatory reactivity of microglia in the brain.…”