Figure 1.

ISR mediates synaptic and memory impairment triggered by ApoE4 and AβOs. ISR comprises the activation of PKR, GCN2, or PERK, resulting in abnormal eIF2α-P. ApoE4 and AβOs promote an inflammatory process, which likely enhances ISR through PKR-dependent eIF2α-P. PERK and GCN2 may further contribute to the increase eIF2α-P levels. This process favors upregulation of ATF4, whose nuclear actions antagonize CREB activity and facilitate stress-related gene transcription, including CHOP and molecular chaperones. Such transcriptional changes result in defective synaptic plasticity and cognition, and may further stimulate ISR. Aberrant ISR may thus comprise a common ground to explain memory loss in AD, possibly offering novel targets for therapeutic intervention.