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GSK3 inhibitors show benefits in an Alzheimer's disease (AD) model of neurodegeneration but adverse effects in control animals.
Hu, Shuxin; Begum, Aynun N; Jones, Mychica R; Oh, Mike S; Beech, Walter K; Beech, Beverly Hudspeth; Yang, Fusheng; Chen, Pingping; Ubeda, Oliver J; Kim, Peter C; Davies, Peter; Ma, Qiulan; Cole, Greg M; Frautschy, Sally A.
Afiliação
  • Hu S; Greater Los Angeles Healthcare System, Geriatric Research Education and Clinical Center, Veteran's Affairs Medical Center, USA.
Neurobiol Dis ; 33(2): 193-206, 2009 Feb.
Article em En | MEDLINE | ID: mdl-19038340
ABSTRACT
The dysregulation of glycogen synthase kinase-3 (GSK3) has been implicated in Alzheimer disease (AD) pathogenesis and in Abeta-induced neurotoxicity, leading us to investigate it as a therapeutic target in an intracerebroventricular Abeta infusion model. Infusion of a specific GSK3 inhibitor SB216763 (SB) reduced a downstream target, phospho-glycogen synthase 39%, and increased glycogen levels 44%, suggesting effective inhibition of enzyme activity. Compared to vehicle, Abeta increased GSK3 activity, and was associated with elevations in levels of ptau, caspase-3, the tau kinase phospho-c-jun N-terminal kinase (pJNK), neuronal DNA fragmentation, and gliosis. Co-infusion of SB corrected all responses to Abeta infusion except the induction of gliosis and behavioral deficits in the Morris water maze. Nevertheless, SB alone was associated with induction of neurodegenerative markers and behavioral deficits. These data support a role for GSK3 hyperactivation in AD pathogenesis, but emphasize the importance of developing inhibitors that do not suppress constitutive activity.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Quinase 3 da Glicogênio Sintase / Inibidores Enzimáticos / Doença de Alzheimer / Indóis / Maleimidas Limite: Animals Idioma: En Ano de publicação: 2009 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Quinase 3 da Glicogênio Sintase / Inibidores Enzimáticos / Doença de Alzheimer / Indóis / Maleimidas Limite: Animals Idioma: En Ano de publicação: 2009 Tipo de documento: Article