An important aspect of chronic neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, Huntington’s or prion disease, is the generation of an innate inflammatory reaction within the central nervous system. Microglial cells play a leading role in the development and maintenance of this inflammatory reaction, showing enhanced proliferation and morphological activation. Moreover, during neurodegeneration and inflammation, the mechanisms that control neural stem cell biology are altered and may also affect disease progression, causing impaired neural stem cell renewal, migration and differentiation. Since these proliferative responses are both involved in neurodegeneration they may share common or perhaps antagonistic regulatory pathways.In this project, using a tractable laboratory model of neurodegeneration (murine prion disease), we will study the time-course and molecular regulation of microglial and neural stem cell proliferative responses. Moreover, we will analyze the role of the inflammatory milieu in the regulation of the proliferative responses, in order to throw light on the progression of chronic neurodegeneration. These objectives will be addressed using a multidisciplinary technical approach, combining the use of transgenic animal models with cell culture systems, analyzed by cellular and molecular biology techniques. Furthermore, we will cross-validate our studies with the analysis of the microglial and neural stem cell proliferative responses in post-mortem brain samples from Alzheimer’s disease patients. This powerful combined approach would permit us to obtain results that will contribute to the understanding of mechanisms that drive progression of chronic neurodegeneration.