Modulation of microglial activation state following passive immunization in amyloid depositing transgenic mice

Alzheimer's disease is a large and growing health problem. Several lines of transgenic mice overexpressing the amyloid precursor protein (APP) develop both diffuse and compacted amyloid deposits which increase in size and number with age. In the vicinity of compacted deposits, these mice develop neuritic dystrophy and activation of glia. Ultimately, these mice also develop memory deficits. Immunotherapy against the Abeta peptide has been effective in both clearing amyloid deposits from the brain, and improving the mnemonic performance of the transgenic mice. Associated with these actions, are changes in the expression of microglial markers. In some cases, the glial activation markers decline, consistent with reduced provocation from amyloid deposits. However, in a time course study, we found that some markers of microglial activation increase transiently once the immunotherapy is initiated. Still another marker continues to rise for up to 3 months of treatment, and remains elevated even after the parenchymal amyloid deposits are largely removed. These changes are consistent with a shift in the microglial phenotype, transitioning from a condition associated with inflammation and ineffective in clearing Abeta deposits to one with reduced inflammation, and capable of clearing deposited amyloid.