CREB3L2-ATF4 heterodimerization defines a transcriptional hub of Alzheimer's disease gene expression linked to neuropathology

Gene expression is changed by disease, but how these molecular responses arise and contribute to pathophys-iology remains less understood. We discover that beta-amyloid, a trigger of Alzheimer's disease (AD), promotes the formation of pathological CREB3L2-ATF4 transcription factor heterodimers in neurons. Through a multilevel ap-proach based on AD datasets and a novel chemogenetic method that resolves the genomic binding profile of dimeric transcription factors (ChIPmera), we find that CREB3L2-ATF4 activates a transcription network that in-teracts with roughly half of the genes differentially expressed in AD, including subsets associated with beta- amyloid and tau neuropathologies. CREB3L2-ATF4 activation drives tau hyperphosphorylation and secretion in neurons, in addition to misregulating the retromer, an endosomal complex linked to AD pathogenesis. We further provide evidence for increased heterodimer signaling in AD brain and identify dovitinib as a candidate molecule for normalizing beta-amyloid-mediated transcriptional responses. The findings overall reveal differential transcription factor dimerization as a mechanism linking disease stimuli to the development of pathogenic cel-lular states.

Automated summary

In this study, it was found that beta-amyloid, a trigger of Alzheimer's disease (AD), promotes the formation of pathological CREB3L2-ATF4 transcription factor heterodimers in neurons. Through the use of AD datasets and a novel chemogenetic method, the researchers discovered that this heterodimer activates a transcription network interacting with genes differentially expressed in AD, including those associated with beta-amyloid and tau neuropathologies. The activation of CREB3L2-ATF4 also leads to tau hyperphosphorylation and secretion, as well as misregulation of the retromer, a complex linked to AD pathogenesis.