The Role of KLF4 in Alzheimer’s Disease

Cheng, Ziqian; Zou, Xiaohan; Jin, Yang; Gao, Shengxiang; Lv, Jiayin; Li, Bingjin; Cui, Ranji

doi:10.3389/fncel.2018.00325

Cited by 43 publications

(33 citation statements)

References 108 publications

(124 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Analysis of transcription factors identified KLF4 as a common regulator in AD, VaD and FTD. The role of KLF4 as potential therapeutic target in AD has been proposed [54]. Silencing of KLF4 attenuated the release of proinflammatory cytokines caused by accumulation of Aβ42 oligomers in a cellular model of AD [55].…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic and Network Analysis Identifies Shared and Unique Pathways across Dementia Spectrum Disorders

Santiago¹,

Bottero

Potashkin

2020

IJMS

View full text Add to dashboard Cite

Background: Dementia is a growing public health concern with an estimated prevalence of 50 million people worldwide. Alzheimer’s disease (AD) and vascular and frontotemporal dementias (VaD, FTD), share many clinical, genetical, and pathological features making the diagnosis difficult. Methods: In this study, we compared the transcriptome from the frontal cortex of patients with AD, VaD, and FTD to identify dysregulated pathways. Results: Upregulated genes in AD were enriched in adherens and tight junctions, mitogen-activated protein kinase, and phosphatidylinositol 3-kinase and protein kinase B/Akt signaling pathways, whereas downregulated genes associated with calcium signaling. Upregulated genes in VaD were centered on infectious diseases and nuclear factor kappa beta signaling, whereas downregulated genes are involved in biosynthesis of amino acids and the pentose phosphate pathway. Upregulated genes in FTD were associated with ECM receptor interactions and the lysosome, whereas downregulated genes were involved in glutamatergic synapse and MAPK signaling. The transcription factor KFL4 was shared among the 3 types of dementia. Conclusions: Collectively, we identified similarities and differences in dysregulated pathways and transcription factors among the dementias. The shared pathways and transcription factors may indicate a potential common etiology, whereas the differences may be useful for distinguishing dementias.

show abstract

Section: Discussionmentioning

confidence: 99%

Transcriptomic and Network Analysis Identifies Shared and Unique Pathways across Dementia Spectrum Disorders

Santiago¹,

Bottero

Potashkin

2020

IJMS

View full text Add to dashboard Cite

show abstract

“…KLF4, a transcription factor and cell-cycle suppressor, has been shown to be implicated in various human diseases ( Wang et al, 2016 , 2018 ; Xu et al, 2020 ). In addition, KLF4 was uncovered to be relevant to the pathogenesis of Alzheimer’s disease ( Cheng et al, 2018 ). Previous evidence also reported that KLF4 silencing protected against MPP + -evoked cytotoxicity in PD ( Chen et al, 2013 ; Kong et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Knockdown of SNHG14 Alleviates MPP+-Induced Injury in the Cell Model of Parkinson’s Disease by Targeting the miR-214-3p/KLF4 Axis

et al. 2020

View full text Add to dashboard Cite

Background: Parkinson's disease (PD) is the second most common neurodegenerative disease. Long non-coding RNA (lncRNA) small nucleolar RNA host gene 14 (SNHG14) has been demonstrated as an important regulator in PD pathology. However, the functional mechanisms played by SNHG14 in PD remain largely unclear. Methods: We used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1methyl-4-phenylpyridinium (MPP +) to establish PD mouse and cell models. The levels of SNHG14, miR-214-3p, and Krüppel-like factor 4 (KLF4) were gauged by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot analysis. Cell viability and apoptosis were determined using the Cell Counting-8 Kit (CCK-8) assay and flow cytometry, respectively. The levels of inflammatory cytokines were evaluated by ELISA. The relationships among SNHG14, miR-214-3p, and KLF4 were confirmed by dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. Results: Our data indicated that SNHG14 was upregulated and miR-214-3p was downregulated in PD models. SNHG14 knockdown ameliorated MPP +-stimulated damage in SK-N-SH cells, as evidenced by the enhancement in cell viability and the suppression in cell apoptosis and pro-inflammatory cytokine production. Mechanistically, SNHG14 directly targeted miR-214-3p via binding to miR-214-3p, and SNHG14 knockdown protected SK-N-SH cell from MPP +-stimulated cytotoxicity by upregulating miR-214-3p. KLF4 was a direct target of miR-214-3p, and SNHG14 regulated KLF4 expression by acting as a miR-214-3p sponge. Furthermore, miR-214-3p overexpression alleviated MPP +-stimulated damage in SK-N-SH cells by downregulating KLF4. Conclusion: Our current study first demonstrated the protective effect of SNHG14 knockdown on MPP +-stimulated cytotoxicity in SK-N-SH cells at least partially by targeting the miR-214-3p/KLF4 axis, illuminating a promising target for PD intervention and treatment.

show abstract

“…Expression of KLF2 and KLF4, which negatively regulate proliferation, inflammation, and angiogenesis, upregulate eNOS, and are sharply downregulated at sites of low and disturbed shear stress, were not different in collaterals versus DMAs. Interestingly, PrC promote Klf2, Klf4 , and eNOS expression [35,36,37,44,69,70].…”

Section: Discussionmentioning

confidence: 99%

Collateral Vessels Have Unique Endothelial and Smooth Muscle Cell Phenotypes

Zhang

Chalothorn

Faber

2019

IJMS

View full text Add to dashboard Cite

Collaterals are unique blood vessels present in the microcirculation of most tissues that, by cross-connecting a small fraction of the outer branches of adjacent arterial trees, provide alternate routes of perfusion. However, collaterals are especially susceptible to rarefaction caused by aging, other vascular risk factors, and mouse models of Alzheimer’s disease—a vulnerability attributed to the disturbed hemodynamic environment in the watershed regions where they reside. We examined the hypothesis that endothelial and smooth muscle cells (ECs and SMCs, respectively) of collaterals have specializations, distinct from those of similarly-sized nearby distal-most arterioles (DMAs) that maintain collateral integrity despite their continuous exposure to low and oscillatory/disturbed shear stress, high wall stress, and low blood oxygen. Examination of mouse brain revealed the following: Unlike the pro-inflammatory cobble-stoned morphology of ECs exposed to low/oscillatory shear stress elsewhere in the vasculature, collateral ECs are aligned with the vessel axis. Primary cilia, which sense shear stress, are present, unexpectedly, on ECs of collaterals and DMAs but are less abundant on collaterals. Unlike DMAs, collaterals are continuously invested with SMCs, have increased expression of Pycard, Ki67, Pdgfb, Angpt2, Dll4, Ephrinb2, and eNOS, and maintain expression of Klf2/4. Collaterals lack tortuosity when first formed during development, but tortuosity becomes evident within days after birth, progresses through middle age, and then declines—results consistent with the concept that collateral wall cells have a higher turnover rate than DMAs that favors proliferative senescence and collateral rarefaction. In conclusion, endothelial and SMCs of collaterals have morphologic and functional differences from those of nearby similarly sized arterioles. Future studies are required to determine if they represent specializations that counterbalance the disturbed hemodynamic, pro-inflammatory, and pro-proliferative environment in which collaterals reside and thus mitigate their risk factor-induced rarefaction.

show abstract

The Role of KLF4 in Alzheimer’s Disease

Cited by 43 publications

References 108 publications

Transcriptomic and Network Analysis Identifies Shared and Unique Pathways across Dementia Spectrum Disorders

Transcriptomic and Network Analysis Identifies Shared and Unique Pathways across Dementia Spectrum Disorders

Knockdown of SNHG14 Alleviates MPP+-Induced Injury in the Cell Model of Parkinson’s Disease by Targeting the miR-214-3p/KLF4 Axis

Collateral Vessels Have Unique Endothelial and Smooth Muscle Cell Phenotypes

Contact Info

Product

Resources

About