Methylene blue improves brain mitochondrial ABAD functions and decreases Aβ in a neuroinflammatory Alzheimer’s disease mouse model

Bibliographic

Year of Publication: 
2016
Contact PI Name: 
Reham M. Abdel-Kader
Contact PI Affiliation: 
Department of Pharmacology & Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
Co-Authors: 
Aya Zakaria, Nabila Hamdi
Primary Reference (PubMED ID): 
Funding Source:
Study Goal and Principal Findings: 

Methylene blue (MB) phase II clinical trials reported improvements in cognitive functions of Alzheimer’s disease (AD) patients. Regarding MB mechanism of action, its antioxidant and mitochondrial protective effects have been previously described. In relation to AD, it has been recently reported that MB reduced amyloid beta (Aβ) levels in AD models. The mitochondrial enzyme amyloid-binding alcohol dehydrogenase (ABAD) has been shown to bind Aβ inducing mitochondrial dysfunction, providing a direct relation between Aβ toxicity and mitochondrial dysfunction occurring in AD. Since it has been reported that inhibiting ABAD protects mitochondrial functions and prevents Aβ-induced toxicity, the aim of the current study was to investigate if the protective effects of MB could be associated with an effect on ABAD levels and functions. The current study shows that MB is able to enhance cell viability, reduce both reactive oxygen species levels and importantly Aβ oligomers in a lipopolysaccharide (LPS) mouse model. Interestingly, ABAD levels were increased in the brains of the LPS mouse model and MB treatment was able to reduce its levels. Given that regulation of the estradiol level is a well-established function of ABAD, brain estradiol level was compared in LPS mouse model and in MB-treated mice. The results of the current study show that MB treatment is able to improve significantly the LPS-induced decrease of estradiol levels in mice brains, indicating its ability to modulate both levels and function of ABAD. These results give a new insight to possible mechanisms of MB in AD.

Therapeutic Agent

Therapeutic Information: 
Therapy Type:

Animal Model

Model Information: 
Species:
Model Type:
Strain/Genetic Background: 
Swiss Albino

Experimental Design

Is the following information reported in the study?: 
Power/Sample Size Calculation
Blinded for Treatment
Pharmacokinetic Measures
Toxicology Measures
Biomarkers
Formulation
Duration of Treatment
Age of Animal at the Beginning of Treatment
Sex as a Biological Variable
Number of Premature Deaths
Statistical Plan
Inclusion/Exclusion Criteria Included
Randomized into Groups
Blinded for Outcome Measures
Pharmacodynamic Measures
ADME Measures
Dose
Route of Delivery
Frequency of Administration
Age of Animal at the End of Treatment
Study Balanced for Sex as a Biological Variable
Number of Excluded Animals
Genetic Background
Conflict of Interest

Outcomes

Outcomes: 
Outcome MeasuredOutcome Parameters
Histopathology
  • Neuritic Plaques
  • Biochemical
  • Amyloid Binding Alcohol Dehydrogenase (ABAD)
  • Brain-beta amyloid oligomers
  • Estradiol
  • Reactive Oxygen Species (ROS)
  • Immunochemistry
  • Brain-beta amyloid deposits
  • Cell Biology
  • Cell Viability