Abstract
201
Objectives: We previously established dual tracer PET imaging of β-amyloid (Aβ) and activated microglia in Alzheimer’s disease (AD) mouse models. Associations between both biomarkers during disease progression of AD are still discussed controversially. The aim of the present longitudinal study was to enlighten the longitudinal association between Aβ and microglial response during aging of APPSL70 mice, an amyloid mouse model, in vivo. A variant baseline age enabled us to perform correlation analysis with the longitudinal biomarker progression over seven months by dual tracer PET. Terminal immunohistochemistry served for interpretation of PET results under consideration of findings at individual plaque and cell level.
Methods: APPSL70 mice (N=17; starting age: 15-38 weeks) and age-matched C57Bl/6 controls (WT) were investigated in a longitudinal design using amyloid (18F-florbetaben) and 18kDa translocator protein (TSPO) PET (18F-GE180). PET was performed at baseline (0 weeks), intermediate (+10 weeks) and terminal (+26 weeks) time points. A frontal cortical volume-of-interest (VOI) with hindbrain white matter reference served for calculation of standardized-uptake-value ratio (SUVRCTX/WM) values. Terminal percentage differences were calculated relative to baseline (Δ-%). Additionally, Z-scores versus WT were calculated for amyloid-PET and TSPO-PET, and the microglial activation relative to amyloidosis was defined as the Z-score difference (TSPO - Aβ). Immunohistochemistry for activated microglia (Iba-1) and fibrillar Aβ (methoxy-X04) were performed with 3D stacks to analyze brain volumes of microglial activation relative to the plaque size and the distance to plaque borders. Results: Relative to the baseline age, an exponential function of Δ-% SUVRCTX/WM was observed in Aβ-PET of APPSL70 mice. Contrary an inverse U-shape was present for Δ-% SUVRCTX/WM of TSPO-PET with a peak increase at a baseline age of 28 weeks. Longitudinal Z-score differences dropped with aging, meaning that less microglial response was observed relative to ongoing amyloidosis in aging APPSL70 mice. Immunohistochemistry revealed that the fraction of activated microglia at the plaque border decreased with increasing plaque size, while the plaque size was associated with age. IBA-1 positive cells in regions without Aβ plaques were significantly lower in APPSL70 mice when compared to WT. Conclusions: Microglial activity decreases relative to ongoing amyloidosis during aging of APPSL70 mice. The plaque-associated microglial fraction showed saturation and correlated with plaque size and aging, most likely related to limited proliferation of microglia, emptying the peripheral reserve.