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Regulation of cellular proliferation in chronic neurodegenerative disease: Microglial proliferation and neurogenesis in prion disease

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Immune responses in prion disease

Prion diseases are a group of progressive neurodegenerative disorders that were initially reported in the 1980's. Thirty years later, scientists are beginning to understand the events that take place during neurodegeneration.

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Prion diseases and neurodegenerative conditions such as Alzheimer's disease (AD) are caused by misfolded proteins. Accumulating evidence suggests that cells of the innate immune system contribute to disease progression. Understanding the interplay between the immune system and the causative agent of neurodegeneration could help unveil novel targets for therapeutic intervention. The work of the EU-funded PRONEURODEG project focused on microglia activation and proliferation in neurodegenerative conditions. Microglia are the brain-resident phagocytes which maintain local homeostasis by supporting neuronal function and clearing apoptotic cells. During chronic neurodegeneration, microglia proliferation was found to be dependent on its interaction with CSF1R receptor and its ligands — CSF1 and interleukin-34. Scientists used a small molecule inhibitor to block this interaction in vivo and detected a rather delayed onset of the clinical and pathological course of prion disease. This coincided with decreased microglial proliferation and urged scientists to study the role of this cell population in other brain diseases. Significant part of the PRONEURODEG work was devoted to the process of neurogenesis in prion disease. Genetic marking of newly developed neurons led researchers to conclude that functional adult neurons are continuously being produced and integrated in the brain during disease progression. These findings were in accordance with observations from post-mortem tissues of patients with variant Creutzfeldt-Jakob disease and AD. Investigation of the impact of the innate immune response on the regulation of adult neurogenesis showed that during chronic neurodegeneration, microglia inhibit neuronal formation. Additionally, gene expression analysis identified a list of microglia-derived regulators of neurogenesis which could serve as therapeutic targets. Collectively, the results of the PRONEURODEG work incriminate microglia and the immune system as key contributors to the progression of neurodegenerative disorders. Based on this, modulation of microglia activation as a clinical intervention could potentially slow down or halt disease progression.

Keywords

Prion diseases, neurodegenerative, innate immune system, microglia, neurogenesis

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