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Methylene blue modulates β-secretase, reverses cerebral amyloidosis, and improves cognition in transgenic mice


Year of Publication:
Contact PI Name:
Terrence Town
Contact PI Affiliation:
Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
Takashi Mori, Naoki Koyama, Tatsuya Segawa, Masahiro Maeda, Nobuhiro Maruyama Noriaki Kinoshita, Huayan Hou, Jun Tan
Primary Reference (PubMED ID):
Funding Source:
National Institute of Neurological Disorders and Stroke (NINDS)
Japan Society for the Promotion of Sciences (JSPS)
Alzheimer's Association
American Federation for Aging Research
Julie Martin Mid-Career Award in Aging
Study Goal and Principal Findings:

Amyloid precursor protein (APP) proteolysis is required for production of amyloid-(A) peptides that comprise-amyloid plaques in the brains of patients with Alzheimer disease (AD). Here, we tested whether the experimental agent methylene blue (MB), used for treatment of methemoglobinemia, might improve AD-like pathology and behavioral deficits. We orally administered MB to the aged transgenic PSAPP mouse model of cerebral amyloidosis and evaluated cognitive function and cerebral amyloid pathology. Beginning at 15 months of age, animals were gavaged with MB (3 mg/kg) or vehicle once daily for 3 months. MB treatment significantly prevented transgene associated behavioral impairment, including hyperactivity, decreased object recognition, and defective spatial working and reference memory, but it did not alter nontransgenic mouse behavior. Moreover, brain parenchymal and cerebral vascular -amyloid deposits as well as levels of various A species, including oligomers, were mitigated in MB-treated PSAPP mice. These effects occurred with inhibition of amyloidogenic APP proteolysis. Specifically, -carboxyl-terminal APP fragment and -site APP cleaving enzyme 1 protein expression and activity were attenuated.These results underscore the potential for oral MB treatment against AD-related cerebral amyloidosis by modulating the amyloidogenic pathway.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Methylthioninium Chloride (MTC)
Therapeutic Target:
Amyloidogenic Proteins

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
Model Type:
Strain/Genetic Background:

Experimental Design

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


Outcome Measured
Outcome Parameters
Exploratory Activity
Novel Object Recognition Test (NORT)
Y Maze
Radial Arm Water Maze
beta Amyloid Deposits
Cerebral Amyloid Angiopathy (CAA)
beta Amyloid Load
Brain-beta Amyloid Oligomers
Brain-beta Amyloid Peptide 40
Brain-beta Amyloid Peptide 42
Amyloid Precursor Protein (APP)
Presenilin 1 (PS1)
beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1)
Presenilin Enhancer 2 (PEN2)
beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1)