Late-stage Anle138b treatment ameliorates tau pathology and metabolic decline in a mouse model of human Alzheimer’s disease tau | Alzheimer's Research & Therapy | Full Text

Late-stage Anle138b treatment ameliorates tau pathology and metabolic decline in a mouse model of human Alzheimer’s disease tau | Alzheimer's Research & Therapy | Full Text

Alzheimer's Research & Therapy

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

• Matthias Brendel, 
• Maximilian Deussing, 
• Tanja Blume, 
• Lena Kaiser, 
• Federico Probst, 
• Felix Overhoff, 
• Finn Peters, 
• Barbara von Ungern-Sternberg, 
• Sergey Ryazanov, 
• Andrei Leonov, 
• Christian Griesinger, 
• Andreas Zwergal, 
• Johannes Levin, 
• Peter Bartenstein, 
• Igor Yakushev, 
• Paul Cumming, 
• Guido Boening, 
• Sibylle Ziegler, 
• Jochen Herms, 
• Armin Giese & 
• Axel Rominger 

Alzheimer's Research & Therapyvolume 11, Article number: 67 (2019) | Download Citation

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.