Journal article
Late-stage Anle138b treatment ameliorates tau pathology and metabolic decline in a mouse model of human Alzheimer's disease tau.
- Brendel M Department of Nuclear Medicine, University Hospital, LMU Munich, Marchioninistr.15, 81377, Munich, Germany. matthias.brendel@med.uni-muenchen.de.
- Deussing M Department of Nuclear Medicine, University Hospital, LMU Munich, Marchioninistr.15, 81377, Munich, Germany.
- Blume T Department of Nuclear Medicine, University Hospital, LMU Munich, Marchioninistr.15, 81377, Munich, Germany.
- Kaiser L Department of Nuclear Medicine, University Hospital, LMU Munich, Marchioninistr.15, 81377, Munich, Germany.
- Probst F Department of Nuclear Medicine, University Hospital, LMU Munich, Marchioninistr.15, 81377, Munich, Germany.
- Overhoff F Department of Nuclear Medicine, University Hospital, LMU Munich, Marchioninistr.15, 81377, Munich, Germany.
- Peters F German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
- von Ungern-Sternberg B Department of Nuclear Medicine, University Hospital, LMU Munich, Marchioninistr.15, 81377, Munich, Germany.
- Ryazanov S Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
- Leonov A Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
- Griesinger C Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
- Zwergal A Department of Neurology, University Hospital, LMU Munich, Munich, Germany.
- Levin J Department of Neurology, University Hospital, LMU Munich, Munich, Germany.
- Bartenstein P Department of Nuclear Medicine, University Hospital, LMU Munich, Marchioninistr.15, 81377, Munich, Germany.
- Yakushev I Neuroimaging Center (TUM-NIC), Technische Universität München, Munich, Germany.
- Cumming P Department of Nuclear Medicine, Inselspital Bern, Bern, Switzerland.
- Boening G Department of Nuclear Medicine, University Hospital, LMU Munich, Marchioninistr.15, 81377, Munich, Germany.
- Ziegler S Department of Nuclear Medicine, University Hospital, LMU Munich, Marchioninistr.15, 81377, Munich, Germany.
- Herms J German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
- Giese A German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
- Rominger A Department of Nuclear Medicine, University Hospital, LMU Munich, Marchioninistr.15, 81377, Munich, Germany.
- 2019-08-03
Published in:
- Alzheimer's research & therapy. - 2019
Anle138b
Late-stage
Neuronal injury
Small animal PET
Tau
Alzheimer Disease
Animals
Benzodioxoles
Disease Models, Animal
Disease Progression
Female
Humans
Mice
Mice, Transgenic
Neurofibrillary Tangles
Positron-Emission Tomography
Pyrazoles
tau Proteins
English
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.
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.
- Language
-
- English
- Open access status
- gold
- Identifiers
-
- DOI 10.1186/s13195-019-0522-z
- PMID 31370885
- Persistent URL
- https://sonar.ch/global/documents/185389
Statistics
Document views: 59
File downloads: