title: 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.affiliation: Departments of Biomedical Sciences and Saitama Medical Center and University, Kawagoe, Saitama 350-8550, Japan; Departments of Pathology, Saitama Medical Center and University, Kawagoe, Saitama 350-8550, Japan,. Electronic address: t_mori@saitama-med.ac.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Mori
authors.affiliation: Departments of Biomedical Sciences and Saitama Medical Center and University, Kawagoe, Saitama 350-8550, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Koyama
authors.affiliation: Immuno-Biological Laboratories Co., Ltd., Fujioka, Gunma 375-0005, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Segawa
authors.affiliation: Immuno-Biological Laboratories Co., Ltd., Fujioka, Gunma 375-0005, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Maeda
authors.affiliation: Immuno-Biological Laboratories Co., Ltd., Fujioka, Gunma 375-0005, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Maruyama
authors.affiliation: Immuno-Biological Laboratories Co., Ltd., Fujioka, Gunma 375-0005, Japan.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Kinoshita
authors.affiliation: Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center and University of South Florida, Tampa, Florida 33613.
authors.forename: Huayan
authors.initials: H
authors.lastname: Hou
authors.affiliation: Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center and University of South Florida, Tampa, Florida 33613; Neuroimmunology Laboratory, Department of Psychiatry and Behavioral Neurosciences, Morsoni College of Medicine, University of South Florida, Tampa, Florida 33613, and.
authors.forename: Jun
authors.initials: J
authors.lastname: Tan
authors.affiliation: Zilkha Neurogenetic Institute, Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California 90089-2821. Electronic address: ttown@usc.edu.
authors.forename: Terrence
authors.initials: T
authors.lastname: Town
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000473:pathology / Q000523:psychology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000686:Amyloidosis / Q000188:drug therapy* / Q000473:pathology / Q000523:psychology; D000818:Animals; D001927:Brain Diseases / Q000188:drug therapy* / Q000473:pathology / Q000523:psychology; D016466:CHO Cells; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003071:Cognition / Q000187:drug effects*; D006224:Cricetinae; D003412:Cricetulus; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008751:Methylene Blue / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D059748:Proteolysis
chemical_list: D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases; D008751:Methylene Blue
keywords: Alzheimer Disease; Amyloid; Amyloid Precursor Protein (APP); Animal Model; Anti-amyloidogenic; Methylene Blue; Secretase; Transgenic Mouse; β-Secretase