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

Alzheimers Res Ther. 2019 Aug 1;11(1):67. doi: 10.1186/s13195-019-0522-z.

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.

Publication types

  • Randomized Controlled Trial, Veterinary
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / diagnostic imaging
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism*
  • Animals
  • Benzodioxoles / administration & dosage
  • Benzodioxoles / pharmacology*
  • Disease Models, Animal
  • Disease Progression
  • Female
  • Humans
  • Mice
  • Mice, Transgenic
  • Neurofibrillary Tangles / drug effects*
  • Neurofibrillary Tangles / metabolism*
  • Positron-Emission Tomography
  • Pyrazoles / administration & dosage
  • Pyrazoles / pharmacology*
  • tau Proteins / metabolism*

Substances

  • 3-(1,3-benzodioxol-5-yl)-5-(3-bromophenyl)-1H-pyrazole
  • Benzodioxoles
  • Pyrazoles
  • tau Proteins