GSK3 inhibitors show benefits in an Alzheimer's disease (AD) model of neurodegeneration but adverse effects in control animals

NEUROBIOLOGY OF DISEASE

卷:33

Article

Hu, Shuxin¹  Begum, Aynun N.¹  Jones, Mychica R.¹  Oh, Mike S.¹  Beech, Walter K.¹  Beech, Beverly Hudspeth¹  Yang, Fusheng¹  Chen, Pingping¹  Ubeda, Oliver J.¹  Kim, Peter C.¹  Davies, Peter³  Ma, Qiulan¹  Cole, Greg M.^1,2  Frautschy, Sally A.^1,2 

[1] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA

[2] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA

[3] Albert Einstein Coll, New York, NY USA

关键词: GSK3;    c-jun N-terminal kinase;    Beta-amyloid;    Tau;    Neuron damage;    Alzheimer's;   

DOI  :  10.1016/j.nbd.2008.10.007

来源: Elsevier

【 摘 要 】

The dysregulation of glycogen synthase kinase-3 (GSK3) has been implicated in Alzheimer disease (AD) pathogenesis and in V-induced neurotoxicity, leading us to investigate it as a therapeutic target in an intracerebroventricular A beta 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. A beta 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 A beta 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. Published by Elsevier Inc.

【 授权许可】

Free