EGFR is a potential dual molecular target for cancer and Alzheimer’s disease

Choi, Hee‐Jeong; Jeong, Yoo Joo; Kim, Jieun; Hoe, Hyang‐Sook

doi:10.3389/fphar.2023.1238639

Cited by 18 publications

(6 citation statements)

References 126 publications

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“…Both of these interactions were downregulated in AD. We identified EGFR as an inhibitory neuron receptor in 3 of 4 senders (oligodendrocytes had no overlapping interactions with inhibitory neurons; Fig 4A ), which has been proposed as a therapeutic target in AD [54, 55]. However, ligands targeting EGFR were dependent on the sender cell type.…”

Section: Resultsmentioning

confidence: 97%

Altered Glia-Neuron Communication in Alzheimer’s Disease Affects WNT, p53, and NFkB Signaling Determined by snRNA-seq

Soelter,

Howton,

Clark

et al. 2023

Preprint

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BackgroundAlzheimer’s disease is the most common cause of dementia and is characterized by amyloid-β plaques, tau neurofibrillary tangles, and neuronal loss. Although neuronal loss is a primary hallmark of Alzheimer’s disease, it is known that non-neuronal cell populations are ultimately responsible for maintaining brain homeostasis and neuronal health through neuron-glia and glial cell crosstalk. Many signaling pathways have been proposed to be dysregulated in Alzheimer’s disease, including WNT, TGFβ, p53, mTOR, NFkB, and Pi3k/Akt signaling. Here, we predict altered cell-cell communication between glia and neurons.MethodsUsing public snRNA-sequencing data generated from postmortem human prefrontal cortex, we predicted altered cell-cell communication between glia (astrocytes, microglia, oligodendrocytes, and oligodendrocyte progenitor cells) and neurons (excitatory and inhibitory). We confirmed interactions in an independent orthogonal dataset. We determined cell-type-specificity using Jaccard Similarity Index and investigated the downstream effects of altered interactions in inhibitory neurons through gene expression and transcription factor activity analyses of signaling mediators. Finally, we determined changes in pathway activity in inhibitory neurons.ResultsCell-cell communication between glia and neurons is altered in Alzheimer’s disease in a cell-type-specific manner. As expected, ligands are more cell-type-specific than receptors and targets. We validated 51 ligand- receptor pairs in an independent dataset that included two known Alzheimer’s disease risk genes:APPandAPOE. 17 (14 upregulated and 3 downregulated in Alzheimer’s disease) of the 51 interactions also had the same downstream target gene. Most of the signaling mediators of these interactions were not differentially expressed, however, the mediators that are also transcription factors had differential activity between AD and control. Namely,MYCandTP53, which are associated with WNT and p53 signaling, respectively, had repressor activity in Alzheimer’s disease, along with decreased WNT and p53 activity in inhibitory neurons. Additionally, inhibitory neurons had both increased NFkB signaling pathway activity and activator activity ofNFIL3, an NFkB signaling-associated transcription factor.ConclusionsCell-cell communication between glia and neurons in Alzheimer’s disease is altered in a cell-type-specific manner involving Alzheimer’s disease risk genes. Signaling mediators had altered transcription factor activity suggesting altered glia-neuron interactions may dysregulate signaling pathways including WNT, p53, and NFkB in inhibitory neurons.

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Section: Resultsmentioning

confidence: 97%

Altered Glia-Neuron Communication in Alzheimer’s Disease Affects WNT, p53, and NFkB Signaling Determined by snRNA-seq

Soelter,

Howton,

Clark

et al. 2023

Preprint

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“…It plays a critical role in regulating cell growth, proliferation, and survival. Choi et al (2023) demonstrated the potential therapeutic effects of anti-cancer EGFR tyrosine kinase inhibitors (TKIs) on AD pathology. In AD mouse models, EGFR inhibitors have shown promise in attenuating amyloid-beta (Aβ) pathology and improving cognitive function.…”

Section: Discussionmentioning

confidence: 99%

A review and analysis of key biomarkers in Alzheimer’s disease

Zhang,

Liu,

Zhang

et al. 2024

Front. Neurosci.

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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that affects over 50 million elderly individuals worldwide. Although the pathogenesis of AD is not fully understood, based on current research, researchers are able to identify potential biomarker genes and proteins that may serve as effective targets against AD. This article aims to present a comprehensive overview of recent advances in AD biomarker identification, with highlights on the use of various algorithms, the exploration of relevant biological processes, and the investigation of shared biomarkers with co-occurring diseases. Additionally, this article includes a statistical analysis of key genes reported in the research literature, and identifies the intersection with AD-related gene sets from databases such as AlzGen, GeneCard, and DisGeNet. For these gene sets, besides enrichment analysis, protein–protein interaction (PPI) networks utilized to identify central genes among the overlapping genes. Enrichment analysis, protein interaction network analysis, and tissue-specific connectedness analysis based on GTEx database performed on multiple groups of overlapping genes. Our work has laid the foundation for a better understanding of the molecular mechanisms of AD and more accurate identification of key AD markers.

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“…6 E), it is possible that the exclusively neuronal makeup of our model prevented us from observing potential beneficial effects of EP300/CBP KD. such as the downregulation of noxious agent EGFR, which appears to enact its Aβ42-worsening effect through neuroinflammation and its interaction with glial cells [ 80 , 81 ]. Of particular relevance, our previous study reporting a net increase in H3K27ac in AD brains was performed in whole brain tissue, which does indeed contain glial cell types.…”

Section: Discussionmentioning

confidence: 99%

Histone acetylation in an Alzheimer’s disease cell model promotes homeostatic amyloid-reducing pathways

Xu,

Sas-Nowosielska,

Donahue

et al. 2024

acta neuropathol commun

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Alzheimer’s Disease (AD) is a disorder characterized by cognitive decline, neurodegeneration, and accumulation of amyloid plaques and tau neurofibrillary tangles in the brain. Dysregulation of epigenetic histone modifications may lead to expression of transcriptional programs that play a role either in protecting against disease genesis or in worsening of disease pathology. One such histone modification, acetylation of histone H3 lysine residue 27 (H3K27ac), is primarily localized to genomic enhancer regions and promotes active gene transcription. We previously discovered H3K27ac to be more abundant in AD patient brain tissue compared to the brains of age-matched non-demented controls. In this study, we use iPSC-neurons derived from familial AD patients with an amyloid precursor protein (APP) duplication (APPDup neurons) as a model to study the functional effect of lowering CBP/P300 enzymes that catalyze H3K27ac. We found that homeostatic amyloid-reducing genes were upregulated in the APPDup neurons compared to non-demented controls. We lowered CBP/P300 to reduce H3K27ac, which led to decreased expression of numerous of these homeostatic amyloid-reducing genes, along with increased extracellular secretion of a toxic amyloid-β species, Aβ(1–42). Our findings suggest that epigenomic histone acetylation, including H3K27ac, drives expression of compensatory genetic programs in response to AD-associated insults, specifically those resulting from APP duplication, and thus may play a role in mitigating AD pathology in neurons.

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EGFR is a potential dual molecular target for cancer and Alzheimer’s disease

Cited by 18 publications

References 126 publications

Altered Glia-Neuron Communication in Alzheimer’s Disease Affects WNT, p53, and NFkB Signaling Determined by snRNA-seq

Altered Glia-Neuron Communication in Alzheimer’s Disease Affects WNT, p53, and NFkB Signaling Determined by snRNA-seq

A review and analysis of key biomarkers in Alzheimer’s disease

Histone acetylation in an Alzheimer’s disease cell model promotes homeostatic amyloid-reducing pathways

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