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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.

SUBMITTER: Gouveia Roque C

PROVIDER: S-EPMC9984184 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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

Gouveia Roque Cláudio C Chung Kyung Min KM McCurdy Ethan P EP Jagannathan Radhika R Randolph Lisa K LK Herline-Killian Krystal K Baleriola Jimena J Hengst Ulrich U

Science advances 20230303 9

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 a ...[more]

PMID: 36867706

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Project description:The key pathological hallmarks-extracellular plaques and intracellular neurofibrillary tangles (NFT)-described by Alois Alzheimer in his seminal 1907 article are still central to the postmortem diagnosis of Alzheimer's disease (AD), but major advances in our understanding of the underlying pathophysiology as well as significant progress in clinical diagnosis and therapy have changed the perspective and importance of neuropathologic evaluation of the brain. The notion that the pathological processes underlying AD already start decades before symptoms are apparent in patients has brought a major change reflected in the current neuropathological classification of AD neuropathological changes (ADNC). The predictable progression of beta-amyloid (Aβ) plaque pathology from neocortex, over limbic structures, diencephalon, and basal ganglia, to brainstem and cerebellum is captured in phases described by Thal and colleagues. The progression of NFT pathology from the transentorhinal region to the limbic system and ultimately the neocortex is described in stages proposed by Braak and colleagues. The density of neuritic plaque pathology is determined by criteria defined by the Consortium to establish a registry for Alzheimer's diseases (CERAD). While these changes neuropathologically define AD, it becomes more and more apparent that the majority of patients present with a multitude of additional pathological changes which are possible contributing factors to the clinical presentation and disease progression. The impact of co-existing Lewy body pathology has been well studied, but the importance of more recently described pathologies including limbic-predominant age-related TDP-43 encephalopathy (LATE), chronic traumatic encephalopathy (CTE), and aging-related tau astrogliopathy (ARTAG) still needs to be evaluated in large cohort studies. In addition, it is apparent that vascular pathology plays an important role in the AD patient population, but a lack of standardized reporting criteria has hampered progress in elucidating the importance of these changes for clinical presentation and disease progression. More recently a key role was ascribed to the immune response to pathological protein aggregates, and it will be important to analyze these changes systematically to better understand the temporal and spatial distribution of the immune response in AD and elucidate their importance for the disease process. Advances in digital pathology and technologies such as single cell sequencing and digital spatial profiling have opened novel avenues for improvement of neuropathological diagnosis and advancing our understanding of underlying molecular processes. Finally, major strides in biomarker-based diagnosis of AD and recent advances in targeted therapeutic approaches may have shifted the perspective but also highlight the continuous importance of postmortem analysis of the brain in neurodegenerative diseases.

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Dataset Information

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

Publications

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

Similar Datasets

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