Abstract

During the progression of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and prion diseases there is an innate immune response in the brain. This innate immune response is characterised by proliferation and activation of the microglia. The contribution of these activated microglia to disease progression is much debated. We have studied murine prion disease as a tractable laboratory model of chronic progressive neurodegenerative disease. Early in the disease the microglia become morphologically activated but have an anti-inflammatory, apparently benign, phenotype. However, systemic inflammation has a profound impact on the phenotype of these microglia, that are ‘primed’ by the ongoing neurodegeneration, and switches them from an anti-inflammatory to a pro-inflammatory phenotype with exacerbation of symptoms and an increased rate of progression of disease. In patients with Alzheimer’s disease we have shown that systemic inflammation and infections are associated with more rapid cognitive decline and exacerbation of symptoms. Understanding how systemic co-morbidities contribute to disease progression offers a route to slowing disease progression and improving the quality of life of those with neurodegenerative disease.