Innate Immune Activation in Mouse Models of Amyloidosis and Tauopathy

Abstract

For many years scientists have felt that innate immune activation in the brain (some call this inflammation) played a role in Alzheimer's dementia, and may provide a useful drug target. This hypothesis has been reinforced by the genetic studies which identified many innate immune gene variants that modulate the risk of developing Alzheimer's. Our initial studies testing the hypothesis examined immune activation in models of amyloidosis using lipopolysaccharide and vaccination. Surprisingly, both led to reduced amyloidosis. Additional studies regulated immune activation using gene therapy in both models of amyloidosis and tauopathy. In many instances, an intervention that benefited amyloidosis was found to exacerbate tauopathy and vice versa. In studies of innate immune markers in human CSF, there are some biomarkers that are lower in individuals who are amyloid positive compared to those without amyloid, but which increase in cases with both amyloid and tau positivity. Although the results regarding central nervous system innate immune activation are sometimes discordant with respect to amyloid or tau pathology, recent data find that systemic immune activation by serial exposures to PAMPs, results in both increased tau pathology and increased amyloid pathology. In conclusion, innate immune activation can have differential effects on amyloidosis or tauopathy and the effects of central and systemic inflammation may also be different. Specific targeting of select aspects of innate immunity will be necessary at different stages of the disease to moderate the progression of Alzheimer's disease.