Bibliographic
This study investigated the effects of chronic administration of an inhibitor of the β-site amyloid precursor protein -cleaving enzyme 1 (BACE1) on Alzheimer’s- related pathology by multi-tracer positron emission tomography (PET) imaging in APPPS1-21 mice. Wild-type (WT) and APPPS1-21 (TG) mice received vehicle (VEH) or BACE inhibitor (60 mg/kg) initiated at 7 weeks of age. Outcome measures of brain metabolism, neuroinflammation and amyloid-β pathology were obtained through μPET imaging with 18F-FDG, 18F-PBR111 and 18F-AV45 respectively. Baseline scans were acquired at 6-7 weeks of age and follow-up scans at 4, 7 and 12 months. 18F-AV45 uptake was measured at 8 and 13 months of age. After the final scans histological measures of amyloid-β (4G8), microglia (Iba-1), astrocytes (GFAP) and neuronal nuclei (NeuN) were performed. TG mice demonstrated significant age-associated increases 18FAV45 uptake. An effect of treatment was observed in the cortex (p = 0.0014), hippocampus (p = 0.0005) and thalamus (p < 0.0001). Histology confirmed reduction of amyloid-β pathology in TG-BACE mice. Regardless of treatment, TG mice demonstrated significantly lower 18F-FDG uptake than WT mice in the thalamus (p = 0.0004) and hippocampus (p = 0.0332). NeuN staining was lower in both TG groups in the thalamus and cortex. 18F-PBR111 detected a significant age-related increase in TG mice (p < 0.0001) but did not detect the treatment induced reduction in activated microglia as demonstrated by histology. While 18F-FDG, 18F-PBR111 and 18F-AV45 all detected pathological alterations between TG and WT mice, only 18F-AV45 could detect an effect of BACE inhibitor treatment. However, changes in WT binding of 18F-AV45 undermine the specificity of this effect.