Early and Longitudinal Microglial Activation but Not Amyloid Accumulation Predicts Cognitive Outcome in PS2APP Mice

Neuroinflammation may have beneficial or detrimental net effects on the cognitive outcome of Alzheimer's disease patients (AD). 18kDa translocator protein (TSPO) imaging by positron-emission-tomography (PET) enables longitudinal monitoring of microglial activation in vivo. We compiled serial PET measures of TSPO and amyloid with terminal cognitive assessment (water maze) in an AD transgenic mouse model (PS2APP) from eight to 13 months of age, followed by immunohistochemical analyses of microglia, amyloid and synaptic density. Better cognitive outcome and higher synaptic density in PS2APP mice was predicted by higher TSPO expression at eight months. The progression of TSPO activation to 13 months also showed a moderate association with spared cognition, but amyloidosis did not correlate with the cognitive outcome, regardless of the timepoint. This first PET investigation with longitudinal TSPO- and amyloid-PET together with terminal cognitive testing in an AD mouse model indicates that continuing microglial response seems to impart preserved cognitive performance.