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2014 ; 289
(44
): 30303-30317
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Methylene blue modulates ?-secretase, reverses cerebral amyloidosis, and improves
cognition in transgenic mice
#MMPMID25157105
Mori T
; Koyama N
; Segawa T
; Maeda M
; Maruyama N
; Kinoshita N
; Hou H
; Tan J
; Town T
J Biol Chem
2014[Oct]; 289
(44
): 30303-30317
PMID25157105
show ga
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. Additionally, treatment of
Chinese hamster ovary cells overexpressing human wild-type APP with MB
significantly decreased A? production and amyloidogenic APP proteolysis. These
results underscore the potential for oral MB treatment against AD-related
cerebral amyloidosis by modulating the amyloidogenic pathway.
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