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. 2019 Aug 1;11(1):67.
doi: 10.1186/s13195-019-0522-z.

Late-stage Anle138b treatment ameliorates tau pathology and metabolic decline in a mouse model of human Alzheimer's disease tau

Matthias Brendel  1 , Maximilian Deussing  2 , Tanja Blume  2   3 , Lena Kaiser  2 , Federico Probst  2 , Felix Overhoff  2 , Finn Peters  3 , Barbara von Ungern-Sternberg  2 , Sergey Ryazanov  4 , Andrei Leonov  4   5 , Christian Griesinger  4   6   7 , Andreas Zwergal  8 , Johannes Levin  8   9 , Peter Bartenstein  2   9 , Igor Yakushev  10   11 , Paul Cumming  12   13 , Guido Boening  2 , Sibylle Ziegler  2 , Jochen Herms  3   9   14 , Armin Giese  3   5 , Axel Rominger  2   9   12
Affiliations

Late-stage Anle138b treatment ameliorates tau pathology and metabolic decline in a mouse model of human Alzheimer's disease tau

Matthias Brendel et al. Alzheimers Res Ther. .

Abstract

Background: Augmenting the brain clearance of toxic oligomers with small molecule modulators constitutes a promising therapeutic concept against tau deposition. However, there has been no test of this concept in animal models of Alzheimer's disease (AD) with initiation at a late disease stage. Thus, we aimed to investigate the effects of interventional late-stage Anle138b treatment, which previously indicated great potential to inhibit oligomer accumulation by binding of pathological aggregates, on the metabolic decline in transgenic mice with established tauopathy in a longitudinal 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) study.

Methods: Twelve transgenic mice expressing all six human tau isoforms (hTau) and ten controls were imaged by FDG-PET at baseline (14.5 months), followed by randomization into Anle138b treatment and vehicle groups for 3 months. FDG-PET was repeated after treatment for 3 months, and brains were analyzed by tau immunohistochemistry. Longitudinal changes of glucose metabolism were compared between study groups, and the end point tau load was correlated with individual FDG-PET findings.

Results: Tau pathology was significantly ameliorated by late-stage Anle138b treatment when compared to vehicle (frontal cortex - 53%, p < 0.001; hippocampus - 59%, p < 0.005). FDG-PET revealed a reversal of metabolic decline during Anle138b treatment, whereas the vehicle group showed ongoing deterioration. End point glucose metabolism in the brain of hTau mice had a strong correlation with tau deposition measured by immunohistochemistry (R = 0.92, p < 0.001).

Conclusion: Late-stage oligomer modulation effectively ameliorated tau pathology in hTau mice and rescued metabolic function. Molecular imaging by FDG-PET can serve for monitoring effects of Anle138b treatment.

Keywords: Anle138b; Late-stage; Neuronal injury; Small animal PET; Tau.

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Conflict of interest statement

SR, AL, AG, and CG are inventors in a patent application related to the compound use in this study. AG and CG are co-founders of MODAG. AL is partly employed by MODAG. All other authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Distinct reduction of CP13-positive tau profiles by late-stage Anle138b treatment in hTau mice. Representative immunohistochemistry images of the frontal cortex (a, b) and the hippocampus (c, d) are shown for hTau mice after 3 months treatment with Anle138b or vehicle. Quantification indicated significant reductions of tau load and CP13-positive neurons in the frontal cortex (e, g) and the hippocampus (f, h). Error bars represent SEM
Fig. 2
Fig. 2
Serial FDG-PET imaging of relative cerebral metabolism (SUVR): Cerebral metabolism to FDG-PET improved at follow-up imaging 3 months after initiating late-stage Anle138b treatment in hTau mice when compared to own baseline, with an already established baseline reduction in comparison to non-carrier control mice (a, compare both upper rows). On the other hand, we saw ongoing metabolic decline in the vehicle-treated hTau group (a, compare both lower rows). Quantification of longitudinal changes in relative FDG uptake (ΔSUVR) to PET indicates normalization of cerebral metabolism with prolonged Anle138b administration, but ongoing decrease in the frontal cortex (b) and the hippocampus (c) in the hTau vehicle group. Non-carrier controls do not show any relevant changes of relative FDG uptake over time. Data are adjusted for baseline imaging. BL baseline at 14.5 months of age, FU follow-up at 17.5 months. Error bars represent SEM
Fig. 3
Fig. 3
Voxel-wise analysis of metabolic rescue in the Anle138 treatment group: Direct comparison between follow-up and baseline FDG-PET imaging by statistical parametric mapping of SUVR maps (upper row) as a region-independent analysis. Green coding (coronal slices upon an MRI template) indicates voxels with a significant increase during Anle138b treatment whereas red coding indicates voxels with a significant decrease (p < 0.01; unc; k > 20). SUVR PET images of an individual example are illustrated for baseline (middle row) and follow-up (lower row) time points and show a visually discernible increasing glucose metabolism during treatment
Fig. 4
Fig. 4
Correlation analysis of metabolic function and end point tau assessments: The end point tau burden and the number of CP13-positive neurons per unit area in the frontal cortex had strong negative correlations with end point findings (a, e) and longitudinal changes (c, g) of normalized FDG uptake in hTau mice. Corresponding plots for the hippocampus indicate the same negative correlation between tau burden and region-specific relative glucose metabolism (b, d, f, h). Purple trendlines show the linear association within the hTau treatment group, whereas the gray trendline provides the linear association for the hTau vehicle group. The dashed black line illustrates the linear association of combined hTau mice. Associated R2 values are indicated in the same color. Solid and dotted lines of non-carrier controls show mean ± SEM
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