Evaluation of Small-Animal PET Outcome Measures to Detect Disease Modification Induced by BACE Inhibition in a Transgenic Mouse Model of Alzheimer Disease
| Autor: | Astrid Bottelbergs, Xavier Langlois, Ann Marie Waldron, Steven Staelens, Bianca Van Broeck, Jeroen Verhaeghe, Leonie Wyffels, Steven Deleye, Sigrid Stroobants, Mark E. Schmidt |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Genetically modified mouse Aging medicine.medical_specialty Amyloid beta Hippocampus Mice Transgenic Amyloid Neuropathies Mice 03 medical and health sciences 0302 clinical medicine Alzheimer Disease Fluorodeoxyglucose F18 Internal medicine medicine Animals Aspartic Acid Endopeptidases Humans Radiology Nuclear Medicine and imaging Enzyme Inhibitors Receptor Neuroinflammation Brain Chemistry Inflammation Computer. Automation Calcium metabolism Amyloid beta-Peptides Aniline Compounds biology Glial fibrillary acidic protein Microglia Chemistry Brain Treatment Outcome 030104 developmental biology Endocrinology medicine.anatomical_structure Positron-Emission Tomography biology.protein Ethylene Glycols Amyloid Precursor Protein Secretases Radiopharmaceuticals 030217 neurology & neurosurgery |
| Zdroj: | The Journal of nuclear medicine |
| ISSN: | 2159-662X 0161-5505 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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