AbstractHere we show that human embryonic kidney (HEK) cells stably transfected with amyloid precursor protein (HEK‐APP), expressed a conformational mutant‐like and transcriptionally inactive p53 isoform, and turned out to be less sensitive to the cytotoxin doxorubicin in comparison with untransfected cells. Treatment of HEK‐APP cells with γ‐ and β‐secretase inhibitors prevented generation of unfolded, mutant‐like p53 isoform and made the cells vulnerable to doxorubicin as untransfected cells. Changes in p53 conformational state and reduced sensitivity to doxorubicin were also found in untransfected HEK cells after exposure to nanomolar concentrations of beta‐amyloid (Aβ) and these effects were antagonized by vitamin E. The modulator effects of Aβ on p53 conformational state were, at least in part, due to the intracellular peptides as (i) treatment of HEK‐APP cells with an antibody that sequestered extracellular Aβ did not modify the capability of the cells to express the mutant‐like p53 isoform; (ii) in the presence of 1% serum exogenous Aβ peptide crossed the plasma membrane, as demonstrated by confocal analysis and ELISA, and induced p53 conformational change; and (iii) in the presence of 10% serum Aβ did not enter the cells and consequently did not influence the p53 conformational state.