Microglial response to increasing amyloid load saturates with aging: a longitudinal dual tracer in vivo PET-study

BackgroundCausal associations between microglia activation and -amyloid (A) accumulation during the progression of Alzheimer's disease (AD) remain a matter of controversy. Therefore, we used longitudinal dual tracer in vivo small animal positron emission tomography (PET) imaging to resolve the progression of the association between A deposition and microglial responses during aging of an A mouse model.MethodsAPP-SL70 mice (N=17; baseline age 3.2-8.5months) and age-matched C57Bl/6 controls (wildtype (wt)) were investigated longitudinally for 6months using A (18F-florbetaben) and 18kDa translocator protein (TSPO) PET (18F-GE180). Changes in cortical binding were transformed to Z-scores relative to wt mice, and microglial activation relative to amyloidosis was defined as the Z-score difference (TSPOA). Using 3D immunohistochemistry for activated microglia (Iba-1) and histology for fibrillary A (methoxy-X04), we measure microglial brain fraction relative to plaque size and the distance from plaque margins.ResultsA-PET binding increased exponentially as a function of age in APP-SL70 mice, whereas TSPO binding had an inverse U-shape growth function. Longitudinal Z-score differences declined with aging, suggesting that microglial response declined relative to increasing amyloidosis in aging APP-SL70 mice. Microglial brain volume fraction was inversely related to adjacent plaque size, while the proximity to A plaques increased with age.ConclusionsMicroglial activity decreases relative to ongoing amyloidosis with aging in APP-SL70 mice. The plaque-associated microglial brain fraction saturated and correlated negatively with increasing plaque size with aging.