Evaluation of small-animal PET outcome measures to detect disease modification induced by BACE inhibition in a transgenic mouse model of Alzheimer disease

In this study, we investigated the effects of chronic administration of an inhibitor of the beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) on Alzheimer-related pathology by multitracer PET imaging in transgenic APPPS1-21 (TG) mice. Methods: Wild-type (WT) and TG mice received vehicle or BACE inhibitor (60 mg/kg) starting at 7 wk of age. Outcome measures of brain metabolism, neuroinflammation, and amyloid-beta pathology were obtained through small-animal PET imaging with F-18-FDG, F-18-peripheral benzodiazepine receptor (F-18-PBR), and F-18-florbetapir (F-18-AV45), respectively. Baseline scans were acquired at 6-7 wk of age and follow-up scans at 4, 7, and 12 mo. F-18-AV45 uptake was measured at 8 and 13 mo of age. After the final scans, histologic measures of amyloid-beta (4G8), microglia (ionized calcium binding adaptor molecule 1), astrocytes (glial fibrillary acidic protein), and neuronal nuclei were performed. Results: TG mice demonstrated significant age-associated increases in F-18-AV45 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-beta pathology in TG-BACE mice. Regardless of treatment, TG mice demonstrated significantly lower F-18-FDG uptake than WT mice in the thalamus (P = 0.0004) and hippocampus (P = 0.0332). Neuronal nucleus staining was lower in both TG groups in the thalamus and cortex. F-18-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. Conclusion: Although F-18-FDG, F-18-PBR111, and F-18-AV45 all detected pathologic alterations between TG and WT mice, only F-18-AV45 could detect an effect of BACE inhibitor treatment. However, changes in WT binding of F-18-AV45 undermine the specificity of this effect.

Publication year:2017

Keywords:A1 Journal article

BOF-keylabel:yes

BOF-publication weight:10

CSS-citation score:1

Authors:International

Authors from:Higher Education

Accessibility:Open