Methylene blue does not reverse existing neurofibrillary tangle pathology in the rTg4510 mouse model of tauopathy.
Alzheimer's disease is characterized pathologically by aggregation of amyloid beta into senile plaques and aggregation of pathologically modified tau into neurofibrillary tangles. While changes in amyloid processing are strongly implicated in disease initiation, the recent failure of amyloid-based therapies has highlighted the importance of tau as a therapeutic target. "Tangle busting" compounds including methylene blue and analogous molecules are currently being evaluated as therapeutics in Alzheimer's disease. Previous studies indicated that methylene blue can reverse tau aggregation in vitro after 10 min, and subsequent studies suggested that high levels of drug reduce tau protein levels (assessed biochemically) in vivo. Here, we tested whether methylene blue could remove established neurofibrillary tangles in the rTg4510 model of tauopathy, which develops robust tangle pathology. We find that 6 weeks of methylene blue dosing in the water from 16 months to 17.5 months of age decreases soluble tau but does not remove sarkosyl insoluble tau, or histologically defined PHF1 or Gallyas positive tangle pathology. These data indicate that methylene blue treatment will likely not rapidly reverse existing tangle pathology.
Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129, USA. Electronic address: tara.spires-jones@ed.ac.uk.
Tara L
TL
Spires-Jones
Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129, USA.
Taylor
T
Friedman
McLaughlin Research Institute, Great Falls, MT, USA.
Rose
R
Pitstick
Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129, USA.
Manuela
M
Polydoro
Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129, USA.
Allyson
A
Roe
McLaughlin Research Institute, Great Falls, MT, USA.
George A
GA
Carlson
Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129, USA.
Bradley T
BT
Hyman
D016229:Amyloid beta-Peptides / Q000187:drug effects; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology*; D051379:Mice; D057507:Mice, 129 Strain; D008822:Mice, Transgenic; D016874:Neurofibrillary Tangles / Q000235:genetics / Q000473:pathology*; D024801:Tauopathies / Q000235:genetics / Q000473:pathology*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016875:tau Proteins; D008751:Methylene Blue
Alzheimer; Methylene blue; Tau