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

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.

journal_name

Neurobiol Dis

journal_title

Neurobiology of disease

authors

Hu S,Begum AN,Jones MR,Oh MS,Beech WK,Beech BH,Yang F,Chen P,Ubeda OJ,Kim PC,Davies P,Ma Q,Cole GM,Frautschy SA

doi

10.1016/j.nbd.2008.10.007

subject

Has Abstract

pub_date

2009-02-01 00:00:00

pages

193-206

issue

2

eissn

0969-9961

issn

1095-953X

pii

S0969-9961(08)00252-0

journal_volume

33

pub_type

杂志文章

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