Methylene Blue Modulates {beta}-secretase, Reverses Cerebral Amyloidosis, and Improves Cognition in Transgenic Mice [Molecular Bases of Disease]

August 25th, 2014 by Mori, T., Koyama, N., Segawa, T., Maeda, M., Maruyama, N., Kinoshita, N., Hou, H., Tan, J., Town, T.

Amyloid precursor protein (APP) proteolysis is required for production of amyloid-β (Aβ) peptides that comprise β-amyloid plaques in brains of Alzheimer disease (AD) patients. 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 amyloidosis. 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 did not alter non-transgenic 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.
  • Posted in Journal of Biological Chemistry, Publications
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