One increasingly dominant hypothesis regarding the pathogenesis of Alzheimer dementia is the inflammation hypothesis. In brief, this hypothesis argues that at least some of the neurodegeneration found in this disease is secondary to excessive activation of microglia and astrocytes, resulting in secretion of pro-inflammatory mediators, activation of the complement cascade and degeneration of synapses and neurons. The APP+PS1 transgenic mouse is a model of Aβ amyloid deposition that results in a phenotype resembling some but not all aspects of Alzheimers. Our group has evaluated a number of manipulations designed to both exacerbate and ameliorate the microglial activation in this transgenic model, ranging from LPS injections, administration of anti-Aβ antibodies and treatment with antiinflammatory drugs. Contrary to our original predictions that microglial activation should exacerbate the Alzheimer phenotype in these mice, we find that treatments that cause microglial activation are associated with reduced amyloid loads. These data are discussed in the context of differences between the murine and human immune systems and qualitative differences in the Aβ deposits found in these mouse models compared to human specimens.