Toluidine blue O modifies hippocampal amyloid pathology in a transgenic mouse model of Alzheimer's disease

Biochimie. 2018 Mar:146:105-112. doi: 10.1016/j.biochi.2017.12.004. Epub 2017 Dec 14.

Abstract

Recently, we have demonstrated that toluidine blue O (TBO), a phenothiazine dye, shows inhibitory effects on both cholinesterases and amyloid pathology in Alzheimer's disease (AD) cellular model. In the present study, we aimed to determine the effects of TBO (in a purity of 85%) on amyloid and tau pathologies in a triple transgenic mouse model of AD (3xTg-AD). Beginning at 7.5 (mild pathology) or 13 (severe pathology) months of age, 3xTg-AD mice were treated intraperitoneally with 4 mg/kg TBO or vehicle daily for 30 days. TBO treatment significantly reduced the levels of insoluble Aβ40 and Aβ42 in the hippocampi of mild and severe pathology groups compared to vehicle-treated counterparts. When the levels of full-length amyloid precursor protein (APP) and β-site APP-cleaving enzyme 1 (BACE1) were assessed in 3xTg-AD mice at late pathological stage, no significant changes were observed after TBO treatment. Similarly, TBO did not recover hyperphosphorylation of tau at residues Thr181 and Ser202/Thr205 significantly in soluble and insoluble hippocampal fractions of 3xTg-AD mice. Taken together, the current study is the first in vivo report, to our knowledge, demonstrating that TBO mitigates amyloid pathology in 3xTg-AD mice with no apparent change on tau phosphorylation. Overall, the preliminary data presented here support the possible use of TBO as a disease-modifying drug for AD treatment.

Keywords: 3xTg-AD mice; Alzheimer's disease; Amyloid-β peptide; Cholinesterase inhibitor; Tau hyperphosphorylation; Toluidine blue O.

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Disease Models, Animal
  • Hippocampus / drug effects*
  • Hippocampus / metabolism*
  • Hippocampus / pathology
  • Male
  • Mice
  • Mice, Transgenic
  • Phosphorylation / drug effects
  • Protein Aggregates / drug effects
  • Tolonium Chloride / pharmacology*
  • Tolonium Chloride / therapeutic use
  • tau Proteins / metabolism

Substances

  • Amyloid beta-Peptides
  • Protein Aggregates
  • tau Proteins
  • Tolonium Chloride