Systemic challenge with the TLR3 agonist poly I:C induces amplified IFNα/β and IL-1β responses in the diseased brain and exacerbates chronic neurodegeneration

The role of inflammation in the progression of neurodegenerative disease remains unclear. We have shown that systemic bacterial insults accelerate disease progression in animals and in patients with Alzheimer’s disease. Disease exacerbation is associated with exaggerated CNS inflammatory responses to systemic inflammation mediated by microglia that become ‘primed’ by the underlying neurodegeneration. The impact of systemic viral insults on existing neurodegenerative disease has not been investigated. Polyinosinic:polycytidylic acid (poly I:C) is a toll-like receptor-3 (TLR3) agonist and induces type I interferons, thus mimicking inflammatory responses to systemic viral infection. In the current study we hypothesized that systemic challenge with poly I:C, during chronic neurodegenerative disease, would amplify CNS inflammation and exacerbate disease. Using the ME7 model of prion disease and systemic challenge with poly I:C (12 mg/kg i.p.) we have shown an amplified expression of IFN-α and β and of the pro-inflammatory genes IL-1β and IL-6. Similarly amplified expression of specific IFN-dependent genes confirmed that type I IFNs were secreted and active in the brain and this appeared to have anti-inflammatory consequences. However, prion-diseased animals were susceptible to heightened acute sickness behaviour and acute neurological impairments in response to poly I:C and this treatment also accelerated disease progression in diseased animals without effect in normal animals. Increased apoptosis coupled with double-stranded RNA-dependent protein kinase (PKR) and Fas transcription suggested activation of interferon-dependent, pro-apoptotic pathways in the brain of ME7 + poly I:C animals. That systemic poly I:C accelerates neurodegeneration has implications for the control of systemic viral infection during chronic neurodegeneration and indicates that type I interferon responses in the brain merit further study.