Intracellularly generated amyloid-β peptide counteracts the antiapoptotic function of its precursor protein and primes proapoptotic pathways for activation by other insults in neuroblastoma cells

被引:30
作者
Esposito, L
Gan, L
Yu, GQ
Essrich, C
Mucke, L [1 ]
机构
[1] Univ Calif San Francisco, Gladstone Inst Neurol Dis, San Francisco, CA 94143 USA
[2] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA
关键词
Alzheimer's disease; amyloid; apoptosis; endoplasmic reticulum; neurodegeneration;
D O I
10.1111/j.1471-4159.2004.02816.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
Most mutations in amyloid precursor proteins (APPs) linked to early onset familial Alzheimer's disease (FAD) increase the production of amyloid-beta peptides ending at residue 42 (Abeta42), which are released from APP by beta- and gamma-secretase cleavage. Stably transfected cells expressing wild-type human APP (APP(WT)) were more resistant to apoptosis-inducing treatments than cells expressing FAD-mutant human APP (APP(FAD)). Preventing Abeta42 production with an M5961 mutation (beta-), which blocks beta-secretase cleavage of APP, or by treatment with a gamma-secretase inhibitor increased the resistance of APP(FAD)-expressing cells to apoptosis. Exposing hAPP(FAD/beta-) cells to exogenous Abeta42 or conditioned medium from Abeta42-producing APPFAD cells did not diminish their resistance to apoptosis. Preventing APP from entering the distal secretory pathway, where most Abeta peptides are generated, by retaining APP in the endoplasmic reticulum (ER)/intermediate compartment (IC) increased the resistance of APPFAD-expressing cells to apoptosis and did not alter the resistance of APPWT-expressing cells. p53-mediated gene transactivation after apoptosis-inducing treatments was much stronger in APPFAD cells than in hAPP(WT) or hAPP(FAD/beta-) cells. In contrast, upon induction of ER stress, cells expressing APPFAD, hAPP(FAD/beta-), or APPWT had comparable levels of glucose-regulated protein-78 mRNA, an unfolded protein response indicator. We conclude that Abeta, especially intracellular Abeta, counteracts the antiapoptotic function of its precursor protein and predisposes cells to p53-mediated, and possibly other, proapoptotic pathways.
引用
收藏
页码:1260 / 1274
页数:15
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