Apolipoprotein E and β-amyloid (1-42) regulation of glycogen synthase kinase-3β

被引:80
作者
Cedazo-Mínguez, A [1 ]
Popescu, BO [1 ]
Blanco-Millán, JM [1 ]
Akterin, S [1 ]
Pei, JJ [1 ]
Winblad, B [1 ]
Cowburn, RF [1 ]
机构
[1] Karolinska Inst, Novum, KFC, Neurotec,Sect Expt Geriatr, S-14186 Huddinge, Sweden
关键词
Alzheimer's disease; apolipoprotein E; beta amyloid; glycogen synthase kinase-3 beta; protein kinase B; protein kinase C;
D O I
10.1046/j.1471-4159.2003.02088.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:1152 / 1164
页数:13
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