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Blocking Microglial Proliferation Could Impede Development of Neurodegenerative Disorders

By BiotechDaily International staff writers
Posted on 06 Mar 2013
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A recent paper outlined the molecular pathway that leads to the chronic inflammation of microglia cells that is characteristic of the brains of patients with neurodegenerative disorders such as Alzheimer's or Creutzfeldt-Jakob disease.

Microglia, which constitute about 20% of glial cells, are the resident macrophages of the brain and spinal cord, and thus act as the first and main form of active immune defense in the central nervous system (CNS). Increased levels of CSF1R1 (colony stimulating factor 1 receptor) are found in microglia in Alzheimer's disease and after brain injuries. The increased receptor expression causes microglia to become more active.

Investigators at the University of Southampton (United Kingdom) studied the time course and regulation of microglial proliferation, using a mouse model of prion disease. They reported in the February 20, 2013, issue of the Journal of Neuroscience that the proliferation of resident microglial cells accounted for the expansion of the population during the development of the disease.

The pathway regulated by the activation of CSF1R and the transcription factors PU.1 (spleen focus forming virus (SFFV) proviral integration oncogene spi1) and C/EBPalpha (CCAAT/enhancer-binding protein alpha) were the molecular regulators of the proliferative response, correlating with the chronic human neurodegenerative conditions variant Creutzfeldt-Jakob disease and Alzheimer's disease.

Targeting the activity of CSF1R inhibited microglial proliferation and slowed neuronal damage and disease progression.

Senior author Dr. Diego Gomez-Nicola, a research fellow at the University of Southampton, said, "We have been able to identify that this molecular system is active in human Alzheimer's disease and variant Creutzfeldt-Jakob disease, pointing to this mechanism being universal for controlling microglial proliferation during neurodegeneration. By means of targeting CSF1R with selective inhibitors we have been able to delay the clinical symptoms of experimental prion disease, also preventing the loss of neurons."

"The understanding of microglial biology during neurodegenerative diseases is crucial for the development of potential therapeutic approaches to control the harmful inflammatory reaction," said Dr. Gomez-Nicola. "These potential interventions could modify or arrest neurodegenerative diseases like Alzheimer disease. The future potential outcomes of this line of research would be rapidly translated into the clinics of neuropathology, and would improve the quality of life of patients with these diseases."

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University of Southampton

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