Relationship Between Reactive Astrocytes, by [18F]SMBT-1 Imaging, with Amyloid-Beta, Tau, Glucose Metabolism, and TSPO in Mouse Models of Alzheimer's Disease

Abstract

Reactive astrocytes play an important role in the development of Alzheimer's disease (AD). Here, we aimed to investigate the temporospatial relationships among monoamine oxidase-B, tau and amyloid-β (Aβ), translocator protein, and glucose metabolism by using multitracer imaging in AD transgenic mouse models. Positron emission tomography (PET) imaging with [¹⁸F]SMBT-1 (monoamine oxidase-B), [¹⁸F]florbetapir (Aβ), [¹⁸F]PM-PBB3 (tau), [¹⁸F]fluorodeoxyglucose (FDG), and [¹⁸F]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 on mouse brain tissue slices. [¹⁸F]SMBT-1 and [¹⁸F]florbetapir SUVRs were greater in the cortex and hippocampus of 10-month-old APP/PS1 mice than in those of 5-month-old APP/PS1 mice and wild-type mice. No significant difference in the regional [¹⁸F]FDG or [¹⁸F]DPA-714 SUVRs was observed in the brains of 5- or 10-month-old APP/PS1 mice or wild-type mice. No significant difference in the SUVRs of any tracer was observed between 11-month-old 3×Tg mice and age-matched wild-type mice. A positive correlation between the SUVRs of [¹⁸F]florbetapir and [¹⁸F]DPA-714 in the cortex and hippocampus was observed among the transgenic mice. Immunostaining validated the distribution of MAO-B and limited Aβ and tau pathology in 11-month-old 3×Tg mice; and Aβ deposits in brain tissue from 10-month-old APP/PS1 mice. In summary, these findings provide in vivo evidence that an increase in astrocyte [¹⁸F]SMBT-1 accompanies Aβ accumulation in APP/PS1 models of AD amyloidosis.

Keywords: Alzheimer’s disease; Amyloid-beta; Glia; MAO-B; PET; TSPO; Tau.

Fig. 1

Increased [¹⁸F]florbetapir brain uptake in 10-month-old APP/PS1 mice compared to 5-month-old APP/PS1 mice and age-matched wild-type mice and 3×Tg mice. a-e Images of SUVRs from 5- and 10-month-old wild-type (WT, a, b), 5- and 10-month-old APP/PS1 (c, d), and 11-month-old 3×Tg mice (e). The SUVR scale was 0–2.2. f Quantification of [¹⁸F]florbetapir in WT, APP/PS1, and 3×Tg mice using Cb as the reference region. g There was no difference in [¹¹C]PIB brain uptake between 3×Tg mice and wild-type mice. The SUVR was calculated using the Cb as the reference brain region. BFS, basal forebrain system; BFS, basal forebrain system; Cb, cerebellum

Fig. 2

[¹⁸F]PM-PBB3 brain uptake did not differ between 3×Tg mice and age-matched wild-type mice. a-d Images of SUVRs from 5- and 10-month-old wild-type (WT, a, b), 5-month-old APP/PS1 (c), and 11-month-old 3×Tg mice (d). The SUVR scale was 0–2.2. e Quantification of [¹⁸F]PM-PBB3 in WT and 3×Tg mice using Cb as the reference brain region. BFS, basal forebrain system; Cb, cerebellum

Fig. 3

Increased [¹⁸F]SMBT-1 brain uptake in 10-month-old APP/PS1 mice compared to age-matched wild-type mice. a-e Images of SUVRs from 5- and 10-month-old wild-type (WT, a, b), 5- and 10-month-old APP/PS1 (c, d), and 11-month-old 3×Tg mice (e). The SUVR scale was 0–2.2. f Quantification of [¹⁸F]SMBT-1 in WT, APP/PS1 and 3×Tg mice using Cb as the reference region. BFS, basal forebrain system; Cb, cerebellum

Fig. 4

[¹⁸F]FDG brain uptake was lower in 5-month-old APP/PS1 mice than in age-matched wild-type mice. a-e Images of SUVRs from 5- and 10-month-old wild-type (WT, a, b), 5- and 10-month-old APP/PS1 (c, d), and 11-month-old 3×Tg mice (e). The SUVR scale was 0–1.8. f Quantification of [¹⁸F]FDG using Cb as the reference brain region in WT, APP/PS1, and 3×Tg mice. BFS, basal forebrain system; Cb, cerebellum

Fig. 5

Comparable [¹⁸F]DPA-714 brain uptake in 5-month- and 10-month-old APP/PS1 mice, age-matched wild-type mice and 3×Tg mice. a-e Images of SUVRs from 5- and 10-month-old wild-type (WT, a, b), 5- and 10-month-old APP/PS1 (c, d), and 11-month-old 3×Tg mice (e). The SUVR scale was 0–2.2. f Quantification of the regional [¹⁸F]DPA-714 SUVR using Cb as the reference brain region in WT, APP/PS1 and 3×Tg mice. g, h Correlations between [¹⁸F]florbetapir SUVR and [¹⁸F]DPA-714 SUVR in the cortex (Ctx) and hippocampus (Hip) of mouse brains were assessed using Cb as the reference brain region. BFS, basal forebrain system; Cb, cerebellum

Fig. 6

Immunofluorescence staining of MAO-B and astrocyte markers in mouse brains. Brain tissue sections from wild-type (WT), APP/PS1 and 3×Tg mice were stained for MAO-B (green)/C3D (red)/GFAP (blue). a-j Zoomed-in view showing the colocalization of MAO-B on C3D-positive astrocytes in the subiculum (Sub), cortex (Ctx), thalamus (Thal), and midbrain (MB). k-l Overview of the staining in 3×Tg mice showing the location of the regions (g, h, i, j). Nuclei were counterstained with DAPI (gray). * indicates colocalization. Scale bar = 10 μm (a–j), 1 mm (k), and 200 μm (l)

Fig. 7

Limited amyloid-beta deposits and tau inclusions in the brains of 3×Tg mice and amyloid-beta plaques. a-c Limited amyloid deposits were observed in the subiculum and cortex (layer 3/4) brain tissue sections of 11-month-old 3×Tg mice stained for 6E10 (mainly intracellular); yellow squares in c indicate the locations of the zoomed-in view (a, b). d Amyloid deposits were abundant in the cortex (Ctx) and hippocampus (Hip) and in the thalamus (Thal) of 10-month-old APP/PS1 mice. e, f Limited tau inclusion was observed in the hippocampus (CA1) of 3×Tg mice stained for AT-8. The yellow squares in f indicate the locations enlarged in view (c). The anti-amyloid antibody 6E10 (green) and the anti-phospho-Tau antibody AT-8 (red) were used. Nuclei were counterstained with DAPI (white). Scale bars = 10 mm (a, b, e) and 400 mm (c, d, f)