Relationship between reactive astrocytes, by [18F]SMBT-1 imaging, with amyloid-beta, tau, glucose metabolism, and microgliosis in mouse models of Alzheimer’s disease

Purpose Reactive astrocytes play an important role in the development of Alzheimer’s disease (AD). Here, we aim to investigate the temporospatial relationship between reactive astrocytes, tau and amyloid-β, glucose metabolism, and microgliosis by using multitracer imaging in AD transgenic mouse models. Methods Positron emission tomography (PET) imaging with [ 18 F]SMBT-1 (monoamine oxidase-B), [ 18 F]florbetapir (Aβ), [ 18 F]PM-PBB3 (tau), [ 18 F]FDG, and [ 18 F]DPA-714 (translocator protein) was carried out in 5- and 10-month-old APP/PS1, 11-month-old 3×Tg mice, and aged-matched wild-type mice. The brain regional referenced standard uptake value (SUVR) was computed with the cerebellum as the reference region. Immunofluorescence staining was performed in mouse brain tissue slices. Results [ 18 F]SMBT-1 and [ 18 F]florbetapir SUVRs were higher in the cortex and hippocampus of 10-month-old APP/PS1 mice than in 5-month-old APP/PS1 mice and wild-type mice. Reduced [ 18 F]FDG SUVR was observed in the thalamus and midbrain of 5-month-old APP/PS1 mice compared to wild-type mice. No significant difference in brain regional [ 18 F]DPA-714 SUVR was observed in 5- and 10-month-old APP/PS1 mice compared to wild- type mice. No significant difference in the SUVRs of any tracers was observed in 11-month-old 3×Tg mice compared to age-matched wild-type mice. A positive correlation between the SUVRs of [ 18 F]SMBT-1 and [ 18 F]DPA-714 in the cortex was observed. Immunostaining validated the distribution of MAO-B and TSPO, amyloid and tau inclusions in brain tissue from 10-month-old APP/PS1 mice and limited changes in 11-month- old 3×Tg mice. Conclusion The findings provide in vivo evidence for reactive astrocytes along with amyloid plaque and tau deposition preceding microgliosis in animal models of AD pathologies.