GSK3 inhibitors show benefits in an Alzheimer's disease (AD) model of neurodegeneration but adverse effects in control animals.
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.
Hu
Shuxin
S
Greater Los Angeles Healthcare System, Geriatric Research Education and Clinical Center, Veteran's Affairs Medical Center, USA.
Begum
Aynun N
AN
Jones
Mychica R
MR
Oh
Mike S
MS
Beech
Walter K
WK
Beech
Beverly Hudspeth
BH
Yang
Fusheng
F
Chen
Pingping
P
Ubeda
Oliver J
OJ
Kim
Peter C
PC
Davies
Peter
P
Ma
Qiulan
Q
Cole
Greg M
GM
Frautschy
Sally A
SA
D000544:Alzheimer Disease / Q000139:chemically induced / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D053938:DNA Fragmentation; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D005911:Gliosis / Q000139:chemically induced; D006003:Glycogen / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008301:Maleimides / Q000009:adverse effects / Q000627:therapeutic use*; D018782:Maze Learning; D009410:Nerve Degeneration / Q000188:drug therapy; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; C417521:SB 216763; D016875:tau Proteins; D006003:Glycogen; D048031:JNK Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; C505410:Casp3 protein, rat; D053148:Caspase 3