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

Brendel, M., Deussing, M., Blume, T., Kaiser, L., Probst, F., Overhoff, F., et al. (2019). Late-stage Anle138b treatment ameliorates tau pathology and metabolic decline in a mouse model of human Alzheimer's disease tau. Alzheimer's Research and Therapy, 11(1): 67. doi:10.1186/s13195-019-0522-z.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0004-6751-D Version Permalink: http://hdl.handle.net/21.11116/0000-0004-6754-A
Genre: Journal Article

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 Creators:
Brendel, M., Author
Deussing, M., Author
Blume, T., Author
Kaiser, L., Author
Probst, F., Author
Overhoff, F., Author
Peters, F., Author
von Ungern-Sternberg, B., Author
Ryazanov, S.1, Author              
Leonov, A.2, Author              
Griesinger, C.2, Author              
Zwergal, A., Author
Levin, J., Author
Bartenstein, P., Author
Yakushev, I., Author
Cumming, P., Author
Boening, G., Author
Ziegler, S., Author
Herms, J., Author
Giese, A., Author
Rominger, A., Author more..
Affiliations:
1Department of NMR-based Structural Biology, MPI for biophysical chemistry, Max Planck Society, ou_578567              
2Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society, ou_578567              

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Free keywords: Anle138b; Late-stage; Neuronal injury; Small animal PET; Tau
 Abstract: 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.

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Language(s): eng - English
 Dates: 2019-08-01
 Publication Status: Published online
 Pages: -
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 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1186/s13195-019-0522-z
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Title: Alzheimer's Research and Therapy
Source Genre: Journal
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Pages: 11 Volume / Issue: 11 (1) Sequence Number: 67 Start / End Page: - Identifier: -