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

Abstract

Amyloid precursor protein (APP) proteolysis is required for production of amyloid-β (Aβ) peptides that comprise β-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 β-amyloid deposits as well as levels of various Aβ species, including oligomers, were mitigated in MB-treated PSAPP mice. These effects occurred with inhibition of amyloidogenic APP proteolysis. Specifically, β-carboxyl-terminal APP fragment and β-site APP cleaving enzyme 1 protein expression and activity were attenuated. Additionally, treatment of Chinese hamster ovary cells overexpressing human wild-type APP with MB significantly decreased Aβ production and amyloidogenic APP proteolysis. These results underscore the potential for oral MB treatment against AD-related cerebral amyloidosis by modulating the amyloidogenic pathway.

• Authors: Takashi Mori, Naoki Koyama, Tatsuya Segawa, Masahiro Maeda, Nobuhiro Maruyama, Noriaki Kinoshita, Huayan Hou, Jun Tan, Terrence Town
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 289 Issue 44 Pg. 30303-30317 (Oct 31 2014) ISSN: 1083-351X [Electronic] United States
• PMID: 25157105 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Amyloid beta-Protein Precursor
• Amyloid Precursor Protein Secretases
• Methylene Blue

Topics

• Alzheimer Disease (drug therapy, pathology, psychology)
• Amyloid Precursor Protein Secretases (metabolism)
• Amyloid beta-Protein Precursor (metabolism)
• Amyloidosis (drug therapy, pathology, psychology)
• Animals
• Brain Diseases (drug therapy, pathology, psychology)
• CHO Cells
• Cerebral Cortex (drug effects, metabolism, pathology)
• Cognition (drug effects)
• Cricetinae
• Cricetulus
• Drug Evaluation, Preclinical
• Humans
• Male
• Maze Learning (drug effects)
• Methylene Blue (pharmacology)
• Mice, Inbred C57BL
• Mice, Transgenic
• Proteolysis