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Alzheimers Res Ther. 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.

Author information

1
Department of Nuclear Medicine, University Hospital, LMU Munich, Marchioninistr.15, 81377, Munich, Germany. matthias.brendel@med.uni-muenchen.de.
2
Department of Nuclear Medicine, University Hospital, LMU Munich, Marchioninistr.15, 81377, Munich, Germany.
3
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
4
Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
5
MODAG GmbH, 55324, Wendelsheim, Germany.
6
DFG Research Centre Nanoscale Microscopy and Molecular Physiology of the Brain, 37070, Göttingen, Germany.
7
Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC), University of Göttingen, Göttingen, Germany.
8
Department of Neurology, University Hospital, LMU Munich, Munich, Germany.
9
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
10
Neuroimaging Center (TUM-NIC), Technische Universität München, Munich, Germany.
11
Department of Nuclear Medicine, Technical University of Munich, Munich, Germany.
12
Department of Nuclear Medicine, Inselspital Bern, Bern, Switzerland.
13
School of Psychology and Counselling and IHBI, Queensland University of Technology, Brisbane, Australia.
14
Center for Neuropathology and Prion Research, Ludwig-Maximilians-Universität, Feodor Lynen-Str. 23, 81377, Munich, Germany.

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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