Apolipoprotein E and beta-amyloid (1-42) regulation of glycogen synthase kinase-3beta.
Glycogen synthase kinase-3beta (GSK-3beta) is implicated in regulating apoptosis and tau protein hyperphosphorylation in Alzheimer's disease (AD). We investigated the effects of two key AD molecules, namely apoE (E3 and E4 isoforms) and beta-amyloid (Abeta) 1-42 on GSK-3beta and its major upstream regulators, intracellular calcium and protein kinases C and B (PKC and PKB) in human SH-SY5Y neuroblastoma cells. ApoE3 induced a mild, transient, Ca2+-independent and early activation of GSK-3beta. ApoE4 effects were biphasic, with an early strong GSK-3beta activation that was partially dependent on extracellular Ca2+, followed by a GSK-3beta inactivation. ApoE4 also activated PKC-alpha and PKB possibly giving the subsequent GSK-3beta inhibition. Abeta(1-42) effects were also biphasic with a strong activation dependent partially on extracellular Ca2+ followed by an inactivation. Abeta(1-42) induced an early and potent activation of PKC-alpha and a late decrease of PKB activity. ApoE4 and Abeta(1-42) were more toxic than apoE3 as shown by MTT reduction assays and generation of activated caspase-3. ApoE4 and Abeta(1-42)-induced early activation of GSK-3beta could lead to apoptosis and tau hyperphosphorylation. A late inhibition of GSK-3beta through activation of upstream kinases likely compensates the effects of apoE4 and Abeta(1-42) on GSK-3beta, the unbalanced regulation of which may contribute to AD pathology.
Cedazo-Mínguez
A
A
Neurotec, Section for Experimental Geriatrics, Karolinska Institutet, NOVUM, KFC, plan 4, S-141 86 Huddinge, Sweden. Angel.Cedazo-Mínguez@neurotec.ki.se
Popescu
B O
BO
Blanco-Millán
J M
JM
Akterin
S
S
Pei
J-J
JJ
Winblad
B
B
Cowburn
R F
RF
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000737:chemistry / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016895:Culture Media, Serum-Free / Q000737:chemistry; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D009447:Neuroblastoma / Q000737:chemistry / Q000188:drug therapy / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D020033:Protein Isoforms / Q000737:chemistry / Q000494:pharmacology; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism; D051571:Protein Kinase C-alpha; D017346:Protein Serine-Threonine Kinases; D021381:Protein Transport / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015534:Trans-Activators / Q000378:metabolism; D051176:beta Catenin
D016229:Amyloid beta-Peptides; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; C495270:CTNNB1 protein, human; D016895:Culture Media, Serum-Free; D003598:Cytoskeletal Proteins; D010446:Peptide Fragments; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; C075222:amyloid beta-protein (1-42); D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C496628:PRKCA protein, human; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D038362:Glycogen Synthase Kinase 3; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D002118:Calcium