<p>Alzheimer’s disease (AD) pathology includes transcriptional changes in the neurons, which are in part caused by the heterodimerization of two stress response transcription factors, CREB3L2 and ATF4. We investigated the role of proteasome inhibition and the eIF2α-kinase HRI in the formation of CREB3L2-ATF4 in neurons exposed to soluble oligomeric Aβ₄₂. While HRI activation increased ATF4 expression, it decreased CREB3L2 and CREB3L2-ATF4 levels. Proteasome inhibition, induced by Aβ₄₂, leads to increased levels of both transcription factors in the nucleus. These findings suggest that CREB3L2 levels are normally kept low due to rapid degradation, but proteasome inhibition in response to Aβ₄₂ disrupts this balance, increasing CREB3L2 and heterodimer levels. Activation of HRI not only reduced CREB3L2 and heterodimer levels but also prevented the transcriptional dysregulation of a CREB3L2-ATF4 target, SNX3. Our results suggest that manipulating the HRI pathway during proteasome inhibition could help restore normal gene expression in the context of AD-related protein accumulation.</p>