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Blume, Tanja; Focke, Carola; Peters, Finn; Deussing, Maximilian; Albert, Nathalie L.; Lindner, Simon; Gildehaus, Franz-Josef; Ungern-Sternberg, Barbara von; Ozmen, Laurence; Baumann, Karlheinz; Bartenstein, Peter; Rominger, Axel; Herms, Jochen; Brendel, Matthias (2018): Microglial response to increasing amyloid load saturates with aging: a longitudinal dual tracer in vivo PET-study. In: Journal of Neuroinflammation 15:307
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Background: Causal 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. Methods: APP-SL70 mice (N=17;baseline age 3.2-8.5 months) and age-matched C57Bl/6 controls (wildtype (wt)) were investigated longitudinally for 6 months 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. Results: A-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. Conclusions: Microglial 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.