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

Authors

Brendel M, Deussing M, Blume T, Kaiser L, Probst F, Overhoff F, Peters F, von Ungern-Sternberg B, Ryazanov S, Leonov A, Griesinger C, Zwergal A, Levin J, Bartenstein P, Yakushev I, Cumming, P, Boening G, Ziegler S, Herms J, Giese A, Rominger A

Journal

Alzheimers’s Research and Therapy

Citation

Alzheimers Res Ther. 2019 Aug 1;11(1):67.

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 (18)F-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.