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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
Author(s) -
Esposito Luke,
Gan Li,
Yu GuiQiu,
Essrich Christian,
Mucke Lennart
Publication year - 2004
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2004.02816.x
Subject(s) - amyloid precursor protein , transfection , endoplasmic reticulum , apoptosis , transactivation , alpha secretase , amyloid precursor protein secretase , microbiology and biotechnology , hek 293 cells , p3 peptide , biology , unfolded protein response , chemistry , biochemistry , alzheimer's disease , gene expression , gene , medicine , disease
Most mutations in amyloid precursor proteins (APPs) linked to early onset familial Alzheimer's disease (FAD) increase the production of amyloid‐β peptides ending at residue 42 (Aβ42), which are released from APP by β‐ and γ‐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 Aβ42 production with an M596I mutation (β–), which blocks β‐secretase cleavage of APP, or by treatment with a γ‐secretase inhibitor increased the resistance of APP FAD ‐expressing cells to apoptosis. Exposing hAPP FAD/β– cells to exogenous Aβ42 or conditioned medium from Aβ42‐producing APP FAD cells did not diminish their resistance to apoptosis. Preventing APP from entering the distal secretory pathway, where most Aβ peptides are generated, by retaining APP in the endoplasmic reticulum (ER)/intermediate compartment (IC) increased the resistance of APP FAD ‐expressing cells to apoptosis and did not alter the resistance of APP WT ‐expressing cells. p53‐mediated gene transactivation after apoptosis‐inducing treatments was much stronger in APP FAD cells than in hAPP WT or hAPP FAD/β– cells. In contrast, upon induction of ER stress, cells expressing APP FAD , hAPP FAD/β– , or APP WT had comparable levels of glucose‐regulated protein‐78 mRNA, an unfolded protein response indicator. We conclude that Aβ, especially intracellular Aβ, counteracts the antiapoptotic function of its precursor protein and predisposes cells to p53‐mediated, and possibly other, proapoptotic pathways.