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

Brendel, Matthias; Deussing, Maximilian; Blume, Tanja; Kaiser, Lena; Probst, Federico; Overhoff, Felix; Peters, Finn; Ungern-Sternberg, Barbara von; Ryazanov, Sergey; Leonov, Andrei; Griesinger, Christian; Zwergal, Andreas; Levin, Johannes; Bartenstein, Peter; Yakushev, Igor; Cumming, Paul; Boening, Guido; Ziegler, Sibylle; Herms, Jochen; Giese, Armin und Rominger, Axel (2019): Late-stage Anle138b treatment ameliorates tau pathology and metabolic decline in a mouse model of human Alzheimer's disease tau. In: Alzheimers Research & Therapy, Bd. 11, 67

Abstract

BackgroundAugmenting 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 F-18-fluorodeoxyglucose positron emission tomography (FDG-PET) study.MethodsTwelve transgenic mice expressing all six human tau isoforms (hTau) and ten controls were imaged by FDG-PET at baseline (14.5months), followed by randomization into Anle138b treatment and vehicle groups for 3months. FDG-PET was repeated after treatment for 3months, 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.ResultsTau 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).ConclusionLate-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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin ; Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1758-9193
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198