ArticleScience advances2023
CREB3L2-ATF4 heterodimerization defines a transcriptional hub of Alzheimer's disease gene expression linked to neuropathology.
Article in Science advances, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 24 citations in OpenAlex.
- The Drosophila CEBPG homolog Irbp18 partners with crc (ATF4) to mediate the integrated stress response in degenerative disease models.Cell reports · 2026Article
- Analysis of amyloid beta oligomers by cyclic ion mobility-mass spectrometry.Analytical and bioanalytical chemistry · 2026Article
- Role of Activating Transcription Factor 4 in Metabolic, Neurologic, and Ocular Diseases.Cells · 2026Review
- Transcriptional regulation of human NMNAT2: insights from 3D genome sequencing and bioinformatics.The FEBS journal · 2026Article
- Vesicular Rps6 Released by Astrocytes in an Experimental Model of AD Regulates Local Translation and Enhances Synaptic Integrity in Neurones.Journal of extracellular vesicles · 2025Article
- Cell Type-Specific mTORC1 Signaling and Translational Control in Synaptic Plasticity and Memory.Journal of neurochemistry · 2025Review
- The Relationship Between Diet and the Neuropathological Hallmarks of Alzheimer's Disease in Cognitively Normal Adults: A Systematic Narrative Review.Healthcare (Basel, Switzerland) · 2025Review
- Mendelian Randomization Reveals Unidirectional Links Between Amyloid-β and Tau in Alzheimer's Disease.Dementia and neurocognitive disorders · 2025Article
- The Progress of Cognitive Dysfunction Impairment Caused by Temporal Lobe Epilepsy.Journal of molecular neuroscience : MN · 2025Review
- Modulation of CREB3L2-ATF4 heterodimerization via proteasome inhibition and HRI activation in Alzheimer's disease pathology.Cell death & disease · 2025Article
- The broken Alzheimer's disease genome.Cell genomics · 2024Review
- ATF4 in cellular stress, ferroptosis, and cancer.Archives of toxicology · 2024Review
- Sildenafil as a Candidate Drug for Alzheimer's Disease: Real-World Patient Data Observation and Mechanistic Observations from Patient-Induced Pluripotent Stem Cell-Derived Neurons.Journal of Alzheimer's disease : JAD · 2024Article
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
Gene expression is changed by disease, but how these molecular responses arise and contribute to pathophysiology remains less understood. We discover that β-amyloid, a trigger of Alzheimer's disease (AD), promotes the formation of pathological CREB3L2-ATF4 transcription factor heterodimers in neurons. Through a multilevel approach 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 interacts with roughly half of the genes differentially expressed in AD, including subsets associated with β-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 β-amyloid-mediated transcriptional responses. The findings overall reveal differential transcription factor dimerization as a mechanism linking disease stimuli to the development of pathogenic cellular states.
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