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; von Ungern-Sternberg, Barbara; Ryazanov, Sergey; Leonov, Andrei; Griesinger, Christian; Zwergal, Andreas; Levin, Johannes; Bartenstein, Peter; Yakushev, Igor; Cumming, Paul; Boening, Guido; Ziegler, Sibylle; Herms, Jochen; Giese, Armin; ... (2019). Late-stage Anle138b treatment ameliorates tau pathology and metabolic decline in a mouse model of human Alzheimer’s disease tau. Alzheimer's research & therapy, 11(1), p. 67. BioMed Central 10.1186/s13195-019-0522-z

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Radiology, Neuroradiology and Nuclear Medicine (DRNN) > Clinic of Nuclear Medicine

UniBE Contributor:

Cumming, Paul and Rominger, Axel Oliver

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1758-9193

Publisher:

BioMed Central

Language:

English

Submitter:

Sabine Lanz

Date Deposited:

26 Aug 2019 15:11

Last Modified:

23 Oct 2019 10:47

Publisher DOI:

10.1186/s13195-019-0522-z

PubMed ID:

31370885

BORIS DOI:

10.7892/boris.132444

URI:

https://boris.unibe.ch/id/eprint/132444

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