(A) BACE1-293 cells were incubated for 2 or 24 hrs in either normal DMEM with glucose (4,500 mg/L; CON) or DMEM without glucose (NG; n=3 wells per group). Cells were lysed and 10μg of total protein per lane was used for immunoblot analysis of BACE1, phospho-eIF2α (Ser51), total eIF2α, phospho-c-Jun(Ser63), total c-Jun, phospho-JNK(Thr183/Thr185), total JNK (54kD and 46kD isoforms), phospho-eIF4E(Ser209), and β-actin (see Supplement for list of antibodies used). ~10μg of lysate from UV-treated 293 cells was used as a positive control (+) for induction of stress-response pathways. (B) Immunosignals in (A) were quantified by phosphorimager and normalized in the following ways: BACE1, eIF2α, JNK, and eIF4E-P were normalized to β-actin; eIF2α-P was normalized to total eIF2α ; c-Jun-P was normalized to c-Jun, and JNK-P was normalized to JNK. Values are expressed as percentage of control (CON) for each time-point (error bars = S.E.M.). After 2 hrs of NG treatment, eIF2α-P, c-Jun-P, JNK-P(46kD), and JNK(46kD) were all significantly elevated. At 24 hrs NG, eIF2α-P, c-Jun-P, and JNK-P(46kD) remained elevated, and BACE1, c-Jun, and JNK-P(54kD) became significantly increased as well. eIF4E phosphorylation was unaffected by NG treatments at either time-point. These results show that eIF2α-P is temporally increased before BACE1, as expected if eIF2α-P regulates BACE1 translation. (mean ± SEM; *, p<0.05; **, p<0.01; ***, p<0.001).