C/EBPβ/AEP signaling couples atherosclerosis to the pathogenesis of Alzheimer’s disease

Liao, Jianming; Chen, Guiqin; Liu, Xia; Wei, Zheng Zachory; Yu, Shan-Ping; Chen, Qianxue; Ye, Keqiang

doi:10.1038/s41380-022-01556-0

Cited by 9 publications

(7 citation statements)

References 67 publications

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“…Mice underwent a Morris Water Maze test, including a 2‐day visible platform phase, a 5‐day hidden platform phase, and a day for platform exploration 16 . Motor abilities and exploration behavior of mice were evaluated using open field and object recognition tests.…”

Section: Methodsmentioning

confidence: 99%

“…Mice underwent a Morris Water Maze test, including a 2‐day visible platform phase, a 5‐day hidden platform phase, and a day for platform exploration. 16 Motor abilities and exploration behavior of mice were evaluated using open field and object recognition tests. Trials were conducted three times a day, with a maximum duration of 60 s. Mice failing to reach the platform were guided manually.…”

Section: Methodsmentioning

confidence: 99%

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Meta‐analysis and transcriptomic analysis reveal that NKRF and ZBTB17 regulate the NF‐κB signaling pathway, contributing to the shared molecular mechanisms of Alzheimer's disease and atherosclerosis

Zhang,

Chen,

Shan

2024

CNS Neurosci Ther

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IntroductionAlzheimer's disease (AD) and atherosclerosis (AS) are widespread diseases predominantly observed in the elderly population. Despite their prevalence, the underlying molecular interconnections between these two conditions are not well understood.MethodsUtilizing meta‐analysis, bioinformatics methodologies, and the GEO database, we systematically analyzed transcriptome data to pinpoint key genes concurrently differentially expressed in AD and AS. Our experimental validations in mouse models highlighted the prominence of two genes, NKRF (NF‐κB‐repressing factor) and ZBTB17 (MYC‐interacting zinc‐finger protein 1).ResultsThese genes appear to influence the progression of both AD and AS by modulating the NF‐κB signaling pathway, as confirmed through subsequent in vitro and in vivo studies.ConclusionsThis research uncovers a novel shared molecular pathway between AD and AS, underscoring the significant roles of NKRF and ZBTB17 in the pathogenesis of these disorders.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Meta‐analysis and transcriptomic analysis reveal that NKRF and ZBTB17 regulate the NF‐κB signaling pathway, contributing to the shared molecular mechanisms of Alzheimer's disease and atherosclerosis

Zhang,

Chen,

Shan

2024

CNS Neurosci Ther

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“…Atherosclerosis (ATH) and AD are both age‐dependent inflammatory diseases associated with infiltrating macrophages, vascular pathology, and shared molecular factors. In recent experiments, it has been shown that C/EBPβ‐AEP signaling links atherosclerosis (ATH) to AD by mediating vascular pathology 82 . Inflammatory responses triggered by a high‐fat diet (HFD) activate neuronal C/EBPβ‐AEP signaling, resulting in the development of AD pathology and cognitive impairments 83 .…”

Section: The Molecular Pathway Mechanisms Of C/ebpβ Regulating the Ir...mentioning

confidence: 99%

“…In recent experiments, it has been shown that C/EBPβ‐AEP signaling links atherosclerosis (ATH) to AD by mediating vascular pathology. 82 Inflammatory responses triggered by a high‐fat diet (HFD) activate neuronal C/EBPβ‐AEP signaling, resulting in the development of AD pathology and cognitive impairments. 83 Traumatic brain injury (TBI) induces the activation of the transcription factor C/EBPβ, leading to an upregulation of δ‐secretase expression.…”

Section: The Molecular Pathway Mechanisms Of C/ Ebpβ ...mentioning

confidence: 99%

C/EBPβ: A transcription factor associated with the irreversible progression of Alzheimer's disease

Yao,

Long,

et al. 2024

CNS Neurosci Ther

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BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder distinguished by a swift cognitive deterioration accompanied by distinctive pathological hallmarks such as extracellular Aβ (β‐amyloid) peptides, neuronal neurofibrillary tangles (NFTs), sustained neuroinflammation, and synaptic degeneration. The elevated frequency of AD cases and its proclivity to manifest at a younger age present a pressing challenge in the quest for novel therapeutic interventions. Numerous investigations have substantiated the involvement of C/EBPβ in the progression of AD pathology, thus indicating its potential as a therapeutic target for AD treatment.AimsSeveral studies have demonstrated an elevation in the expression level of C/EBPβ among individuals afflicted with AD. Consequently, this review predominantly delves into the association between C/EBPβ expression and the pathological progression of Alzheimer's disease, elucidating its underlying molecular mechanism, and pointing out the possibility that C/EBPβ can be a new therapeutic target for AD.MethodsA systematic literature search was performed across multiple databases, including PubMed, Google Scholar, and so on, utilizing predetermined keywords and MeSH terms, without temporal constraints. The inclusion criteria encompassed diverse study designs, such as experimental, case–control, and cohort studies, restricted to publications in the English language, while conference abstracts and unpublished sources were excluded.ResultsOverexpression of C/EBPβ exacerbates the pathological features of AD, primarily by promoting neuroinflammation and mediating the transcriptional regulation of key molecular pathways, including δ‐secretase, apolipoprotein E4 (APOE4), acidic leucine‐rich nuclear phosphoprotein‐32A (ANP32A), transient receptor potential channel 1 (TRPC1), and Forkhead BoxO (FOXO).DiscussionThe correlation between overexpression of C/EBPβ and the pathological development of AD, along with its molecular mechanisms, is evident. Investigating the pathways through which C/EBPβ regulates the development of AD reveals numerous multiple vicious cycle pathways exacerbating the pathological progression of the disease. Furthermore, the exacerbation of pathological progression due to C/EBPβ overexpression and its molecular mechanism is not limited to AD but also extends to other neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and multiple sclerosis (MS).ConclusionThe overexpression of C/EBPβ accelerates the irreversible progression of AD pathophysiology. Additionally, C/EBPβ plays a crucial role in mediating multiple pathways linked to AD pathology, some of which engender vicious cycles, leading to the establishment of feedback mechanisms. To sum up, targeting C/EBPβ could hold promise as a therapeutic strategy not only for AD but also for other degenerative diseases.

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“…CCAAT/enhancer-binding protein β (C/EBPβ), a member of the C/EBP family, is an inflammation-associated transcriptional factor involved in neurodegenerative diseases, such as Alzheimer’s disease ( Wang et al, 2018 , 2019 , 2022 ), Parkinson’s disease ( Ahn et al, 2021b ), vascular diseases like cerebral stroke ( Wang R. et al, 2021 ), and atherosclerosis ( Liao et al, 2022 ). It is transcriptionally activated by several inflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor α (TNF-α; Cloutier et al, 2009 ).…”

Section: Introductionmentioning

confidence: 99%

Inflammation-activated C/EBPβ mediates high-fat diet-induced depression-like behaviors in mice

Chen

Wang

et al. 2022

Front. Mol. Neurosci.

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Depression, one of the most common causes of disability, has a high prevalence rate in patients with metabolic syndrome. Type 2 diabetes patients are at an increased risk for depression. However, the molecular mechanism coupling diabetes to depressive disorder remains largely unknown. Here we found that the neuroinflammation, associated with high-fat diet (HFD)-induced diabetes and obesity, activated the transcription factor CCAAT/enhancer binding protein β (C/EBPβ) in hippocampal neurons. This factor repressed brain-derived neurotrophic factor (BDNF) expression and caused depression-like behaviors in male mice. Besides, the loss of C/EBPβ expression in C/EBPβ heterozygous knockout male mice attenuated HFD-induced depression-like behaviors, whereas Thy1-C/EBPβ transgenic male mice (overexpressing C/EBPβ) showed depressive behaviors after a short-term HFD. Furthermore, HFD impaired synaptic plasticity and decreased surface expression of glutamate receptors in the hippocampus of wild-type (WT) mice, but not in C/EBPβ heterozygous knockout mice. Remarkably, the anti-inflammatory drug aspirin strongly alleviated HFD-elicited depression-like behaviors in neuronal C/EBPβ transgenic mice. Finally, the genetic delivery of BDNF or the pharmacological activation of the BDNF/TrkB signaling pathway by 7,8-dihydroxyflavone reversed anhedonia in a series of behavioral tests on HFD-fed C/EBPβ transgenic mice. Therefore, our findings aim to demonstrate that the inflammation-activated neuronal C/EBPβ promotes HFD-induced depression by diminishing BDNF expression.

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C/EBPβ/AEP signaling couples atherosclerosis to the pathogenesis of Alzheimer’s disease

Cited by 9 publications

References 67 publications

Meta‐analysis and transcriptomic analysis reveal that NKRF and ZBTB17 regulate the NF‐κB signaling pathway, contributing to the shared molecular mechanisms of Alzheimer's disease and atherosclerosis

Meta‐analysis and transcriptomic analysis reveal that NKRF and ZBTB17 regulate the NF‐κB signaling pathway, contributing to the shared molecular mechanisms of Alzheimer's disease and atherosclerosis

C/EBPβ: A transcription factor associated with the irreversible progression of Alzheimer's disease

Inflammation-activated C/EBPβ mediates high-fat diet-induced depression-like behaviors in mice

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