Modulation of CREB3L2-ATF4 heterodimerization via proteasome inhibition and HRI activation in Alzheimer's disease pathology.

ABSTRACT: 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. Acti

SUBMITTER: Herline-Killian K 

PROVIDER: S-EPMC11958753 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature