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

Abstract

Background: Alzheimer'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.

Aims: Several 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.

Methods: A 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case-control, and cohort studies, restricted to publications in the English language, while conference abstracts and unpublished sources were excluded.

Results: Overexpression 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).

Discussion: The 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).

Conclusion: The 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.

Keywords: Alzheimer's disease; C/EBPβ; neurodegenerative disease; therapy; transcription.

FIGURE 1

C/EBPβ regulates signaling pathways associated with brain inflammation in AD. C/EBPβ and astrocyte activation: After the activation of astrocytes, the expression of C/EBPβ increases and migrates to the nucleus to regulate gene expression in the nucleus as a transcription factor. C/EBPβ inhibited some ERK1/2 regulatory genes, activated P38K regulatory genes, downregulated ERK1/2 expression, and increased p38K expression, respectively, BDKRB2 expression retention and cox‐2 expression increase in astrocytes. C/EBPβ can also bind to C3, TIMP‐1, and TGF‐β1 promoters to promote their expression. C/EBPβ and microglia activation: After treatment with LPS, IL‐1β, IL‐6, or TNF‐α, C/EBPβ in microglia cells was significantly increased and its transfer to the nucleus was increased. C/EBPβ was bound to pro‐inflammatory gene promoters in a stimulatory and gene‐dependent manner to promote the expression of inflammatory genes in glia activation. iNOS, myeloperoxidase, C‐reactive protein, M‐CSF, and other promoters showed C/EBPβ‐binding sites. Inflammatory factors activate glial cells, induce the increase of C/EBPβ expression, and promote the increase of the expression of more inflammatory factors.

FIGURE 2

The molecular mechanisms underlying the C/EBPβ‐δ‐secretase signaling pathway expedite the progression of AD. The expression of δ‐secretase is regulated by the transcription factor C/EBPβ, which is regulated by the BDNF/TrkB signaling pathway. δ‐secretase is phosphorylated by Akt, which inhibits its activity, and SRPK2, which enhances its activity. The δ‐secretase cleaves APP and promotes the production of Aβ. The δ‐secretase also cleaves Tau, producing fragments that are prone to aggregation. The tau fragment derived from δ‐secretase‐enhanced BACE1 activity, which further promoted the production of Aβ. δ‐secretase‐derived SET fragments inhibit tau dephosphorylation, while δ secretase‐derived SRPK2 fragments affect tau selective splicing. Aβ and APP C586‐695 (C110) fragments ultimately stimulate the transcription of genes associated with AD by binding to and activating C/EBPβ. All of these pathways promote tau aggregation and the occurrence of AD.

FIGURE 3

C/EBPβ mediates the expression of APOE4, leading to the accumulation of lipid droplets and Aβ. The transcription factor C/EBPβ binds and interacts with the C/EBP‐binding motifs within the APOE promoter −305 to +93 fragment, acting as a specific transcription factor for APOE and promoting its gene transcription. ApoE4 can influence lipid transport through an Aβ‐independent pathway, leading to mitochondrial damage and increased reactive oxygen species. Additionally, it can enhance Aβ production through an Aβ‐dependent pathway, concurrently amplifying neuroinflammatory responses. Conversely, ApoE4 strongly activates C/EBPβ, subsequently enhancing δ‐secretase cleavage of the increased APP.

FIGURE 4

C/EBPβ‐TRPC1‐SOCE signaling causes ER stress and dysregulation of protein enzymes and phosphatases. After G protein‐coupled receptors and tyrosine receptors were activated, PLC was subsequently activated to generate IP3 from PIP2. As a calcium channel, IP3R binds to IP3 and is activated, resulting in calcium ion outflow. When Ca²⁺ storage in the ER is depleted, STIM1/2 senses a reduction in Ca²⁺ in the ER, which leads to oligomerization and subsequent transfer from ER‐like sites to the plasma membrane, where it interacts with calcium conduction channels (ORAIs and TRPCs) to induce Ca²⁺ influx and storage regeneration. In the context of hTau overexpression, activated C/EBPβ binds to the TRPC1 promoter sequence, promoting TRPC1 transcription, then increases neuronal steady‐state [Ca²⁺] I, enhances endoplasmic reticulum (ER) stress, imbalances protein kinases, and phosphatases, and exacerbates tauopathy. The C/EBPβ‐Trpc1‐soce‐signaling pathway in turn increases hTau, thus accelerating the progression of AD.

FIGURE 5

The molecular mechanism of C/EBPβ‐ANP32A‐INHAT/PP2A affecting cognitive function. AD‐related stressors increase total C/EBPβ levels and phosphorylated C/EBPβ levels. C/EBPβ induces ANP32 overexpression by binding to conserved recognition elements in the ANP32A proximal promoter region. ANP32A binds to SET to form an inhibitory complex (INHAT) that binds to histones and blocks their acetylation, ultimately resulting in reduced expression of life‐related genes. ANP32A, as an endogenous PP2A inhibitor, can increase the tau hyperphosphorylation level. AD‐like MAPT/Tau accumulation can inhibit autophagosome‐lysosome fusion by regulating the ANP32A‐INHAT‐IST1‐ESCRT‐III pathway, and overexpressed Tau can further promote Cebpb gene expression.

FIGURE 6

Molecular mechanisms of FOXO interact with C/EBPβ to accelerate AD progression. Overexpression of C/EBPβ inhibits REST and FOXO1 promoter activity and reduces REST and FOXO1 transcription. Decreased FOXO/DAF‐16 (abnormal DAuer formation‐16) activity increased insulin signaling, increased Aβ aggregation toxicity, and induced GABAergic neuronal degeneration and death. Inhibition of FOXO gene transcription can promote the transcription of LGMN, which leads to the increase of AEP and the accumulation of Aβ and Tau.