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

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 (APPWT) were more resistant to apoptosis‐inducing treatments than cells expressing FAD‐mutant human APP (APPFAD). 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 APPFAD‐expressing cells to apoptosis. Exposing hAPPFAD/β– cells to exogenous Aβ42 or conditioned medium from Aβ42‐producing APPFAD 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 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 hAPPWT or hAPPFAD/β– cells. In contrast, upon induction of ER stress, cells expressing APPFAD, hAPPFAD/β–, or APPWT 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.

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