Methylene blue modulates ß-secretase, reverses cerebral amyloidosis, and improves cognition in transgenic mice.
J Biol Chem
; 289(44): 30303-30317, 2014 Oct 31.
Article
em En
| MEDLINE
| ID: mdl-25157105
ABSTRACT
Amyloid precursor protein (APP) proteolysis is required for production of amyloid-ß (Aß) peptides that comprise ß-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 ß-amyloid deposits as well as levels of various Aß species, including oligomers, were mitigated in MB-treated PSAPP mice. These effects occurred with inhibition of amyloidogenic APP proteolysis. Specifically, ß-carboxyl-terminal APP fragment and ß-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 Aß production and amyloidogenic APP proteolysis. These results underscore the potential for oral MB treatment against AD-related cerebral amyloidosis by modulating the amyloidogenic pathway.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Encefalopatias
/
Cognição
/
Secretases da Proteína Precursora do Amiloide
/
Amiloidose
/
Azul de Metileno
Idioma:
En
Revista:
J Biol Chem
Ano de publicação:
2014
Tipo de documento:
Article