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

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.

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

“…Concurrently, we also identified significant down regulation of other important genes, such as CREB3L2, MYLK, MYLK4, NPPC, KCNMA1, NPR1 , and GUCY1A1 from cGMP-PKG signaling pathway ( Supplementary Figure 4 ). Recently, CREB3L2-ATF4, a pathological transcription factor heterodimers stated in activating AD transcriptional network and tau hyperphosphorylation [ 68 ]. Interestingly, we also found substantial impact of sildenafil on axon guidance pathway genes ( Supplementary Figure 2 ).…”

Overview of the Molecular Modalities and Signaling Pathways Intersecting with β-Amyloid and Tau Protein in Alzheimer’s Disease

“…Although there is controversy over whether Aβ and/or tau protein are among the major causes of AD pathogenesis [156][157][158], many drugs that target them are being investigated in various clinical trials, with lecanemab and aducanumab approved recently by the FDA (Table 1).…”

The role of membrane trafficking and retromer complex in Parkinson's and Alzheimer's disease

“…This network implicates processes intricately interwoven with β‐amyloid and tau neuropathologies. Notably, the activation of CREB3L2‐ATF4 significantly influences tau hyperphosphorylation, patterns of neuronal secretion, and, critically, the misregulation of the retromer complex—a pivotal nexus in endosomal dynamics that emerges as a compelling contributor to AD pathogenesis (Gouveia Roque et al., 2023).…”