Identification of retinoblastoma binding protein 7 (Rbbp7) as a mediator against tau acetylation and subsequent neuronal loss in Alzheimer’s disease and related tauopathies

Dave, Nikhil; Vural, Austin S.; Piras, Ignazio S.; Winslow, Wendy; Surendra, Likith; Winstone, Joanna K.; Beach, Thomas G.; Huentelman, Matthew J.; Velázquez, Ramón

doi:10.1007/s00401-021-02323-1

Cited by 17 publications

(19 citation statements)

References 60 publications

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“…reported that downregulation of RBBP7 is positively correlated with neuritic plaque density and pathogenic tau inclusions in AD patients. Interestingly, they further demonstrated that increased RBBP7 was protective against tau-related pathogenesis in animal AD models, consistent with clinical observations ( 63 , 64 ). Meanwhile, genome-wide studies illustrated that lots of methylated genes differentiate from the lesion and non-lesion skin of psoriatic patients ( 65 ).…”

Section: Discussionsupporting

confidence: 79%

ZNF384: A Potential Therapeutic Target for Psoriasis and Alzheimer’s Disease Through Inflammation and Metabolism

Liu

Yuan

et al. 2022

Front. Immunol.

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BackgroundPsoriasis is an immune-related skin disease notable for its chronic inflammation of the entire system. Alzheimer’s disease (AD) is more prevalent in psoriasis than in the general population. Immune-mediated pathophysiologic processes may link these two diseases, but the mechanism is still unclear. This article aimed to explore potential molecular mechanisms in psoriasis and AD.MethodsGene expression profiling data of psoriasis and AD were acquired in the Gene Expression Omnibus (GEO) database. Gene Set Enrichment Analysis (GSEA) and single-sample GSEA (ssGSEA) were first applied in two datasets. Differentially expressed genes (DEGs) of two diseases were identified, and common DEGs were selected. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed to explore common biological pathways. Signature transcription factors (STFs) were identified and their diagnostic values was calculated by receiver operating characteristic (ROC) curve analysis in the exploration cohort and verified in the validation cohort. The expression levels of STFs were further investigated in the validation cohort and the GTEx Portal Database. Additionally, four kinds of interaction analysis were performed: correlation analysis among STFs, gene-gene, chemical-protein, and protein-ligand interaction analyses. In the end, we predicted the transcription factor that potentially regulates STFs.ResultsBiosynthesis and metabolic pathways were enriched in GSEA analysis. In ssGSEA analysis, most immunoreaction gene lists exhibited differential enrichment in psoriasis cases, whereas three receptor-related gene lists did in AD. The KEGG analysis of common DEGs redetermined inflammatory and metabolic pathways essential in both diseases. 5 STFs (PPARG, ZFPM2, ZNF415, HLX, and ANHX) were screened from common DEGs. The ROC analysis indicated that all STFs have diagnostic values in two diseases, especially ZFPM2. The correlation analysis, gene-gene, chemical-protein, and protein-ligand interaction analyses suggested that STFs interplay and involve inflammation and aberrant metabolism. Eventually, ZNF384 was the predicted transcription factor regulating PPARG, ZNF415, HLX, and ANHX.ConclusionsThe STFs (PPARG, ZFPM2, ZNF415, HLX, and ANHX) may increase the morbidity rate of AD in psoriasis by initiating a positive feedback loop of excessive inflammation and metabolic disorders. ZNF384 is a potential therapeutic target for psoriasis and AD by regulating PPARG, ZNF415, HLX, and ANHX.

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Section: Discussionsupporting

confidence: 79%

ZNF384: A Potential Therapeutic Target for Psoriasis and Alzheimer’s Disease Through Inflammation and Metabolism

Liu

Yuan

et al. 2022

Front. Immunol.

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“…Twentyfour hours after glyphosate introduction, 0.5 mL of media was collected from the triplicate wells of each treatment and frozen for ELISA analysis of Aβ [40][41][42] . At this same timepoint, the MTT (MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was used to assess cell death as previously described [34]. All absorbance values were normalized to the control group (0 µg/ mL vehicle).…”

Section: In Vitro Experimentsmentioning

confidence: 99%

Glyphosate infiltrates the brain and increases pro-inflammatory cytokine TNFα: implications for neurodegenerative disorders

Winstone

Pathak

Winslow

et al. 2022

J Neuroinflammation

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Background Herbicides are environmental contaminants that have gained much attention due to the potential hazards they pose to human health. Glyphosate, the active ingredient in many commercial herbicides, is the most heavily applied herbicide worldwide. The recent rise in glyphosate application to corn and soy crops correlates positively with increased death rates due to Alzheimer’s disease and other neurodegenerative disorders. Glyphosate has been shown to cross the blood–brain barrier in in vitro models, but has yet to be verified in vivo. Additionally, reports have shown that glyphosate exposure increases pro-inflammatory cytokines in blood plasma, particularly TNFα. Methods Here, we examined whether glyphosate infiltrates the brain and elevates TNFα levels in 4-month-old C57BL/6J mice. Mice received either 125, 250, or 500 mg/kg/day of glyphosate, or a vehicle via oral gavage for 14 days. Urine, plasma, and brain samples were collected on the final day of dosing for analysis via UPLC–MS and ELISAs. Primary cortical neurons were derived from amyloidogenic APP/PS1 pups to evaluate in vitro changes in Aβ40-42 burden and cytotoxicity. RNA sequencing was performed on C57BL/6J brain samples to determine changes in the transcriptome. Results Our analysis revealed that glyphosate infiltrated the brain in a dose-dependent manner and upregulated TNFα in both plasma and brain tissue post-exposure. Notably, glyphosate measures correlated positively with TNFα levels. Glyphosate exposure in APP/PS1 primary cortical neurons increases levels of soluble Aβ40-42 and cytotoxicity. RNAseq revealed over 200 differentially expressed genes in a dose-dependent manner and cell-type-specific deconvolution analysis showed enrichment of key biological processes in oligodendrocytes including myelination, axon ensheathment, glial cell development, and oligodendrocyte development. Conclusions Collectively, these results show for the first time that glyphosate infiltrates the brain, elevates both the expression of TNFα and soluble Aβ, and disrupts the transcriptome in a dose-dependent manner, suggesting that exposure to this herbicide may have detrimental outcomes regarding the health of the general population.

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“…This process included several steps, such as attachment and entry of the virus particle, decoding of genome information and assembly, and release of viral particles containing the genome [32]. To date, studies have reported the role of RBBP7 in several diseases, such as Alzheimer's disease [33] and Wilms Tumor 1 [34], while our results of single-gene GSEA showed that "Fc gamma R-mediated phagocytosis" pathway was significantly enriched in BKVN samples with higher expression levels of RBBP7, which set the foundation for researches of RBBP7 in virus-associated diseases, also in BKVN. After being triggered by clustering of Fc gamma R at sites where leukocytes are bound to the opsonized particles, neutrophils and macrophages engulf IgG-coated particles, which is an essential part of the innate immune response [35].…”

Section: Discussionmentioning

confidence: 99%

Identifying RBBP7 as a Promising Diagnostic Biomarker for BK Virus-Associated Nephropathy

Wang

Zhang

et al. 2022

Journal of Immunology Research

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BK virus-associated nephropathy (BKVN) remains a major infectious complication due to powerful immunosuppression in kidney transplant recipients, and its histologic appearance can mimic rejection, leading to diagnostic and treatment dilemmas thus molecular diagnostic methods would be beneficial. We collected gene expression profiles of 169 kidney biopsies taken from BKVN, rejection, and stable functioning allografts, based on single sample gene set enrichment analysis and random forest algorithm, and three hallmark activities associated with DNA damage and proliferation were found to be relatively specific in BKVN. Subsequently, weighted gene co-expression network analysis and support vector machines (SVM) algorithm identified RBBP7 as a robust and promising biomarker with high accuracy in both training and validation cohorts (AUC =0.938, 0.977, respectively). Besides, potential drugs for BKVN treatment such as mepacrine were discovered, which may contribute to targeted antiviral therapy and effective patient management rather than simply reducing the doses of immunosuppressive agents in clinical practice. RBBP7 (retinoblastoma binding protein 7) serves as component of serval complexes that regulate chromatin metabolism and functions in affecting DNA replication and controlling cell proliferation. In this research, upregulation of RBBP7 was found to be associated with the higher infiltration of CD8 naïve T, iTreg, and neutrophil cells and the lower amounts of Th1, central memory T, NKT, CD8 T, and dendritic cells. Moreover, the infiltration of Th1, Th17, and NKT cells was steadily different between BKVN and rejection allografts through immune cell assessment. In conclusion, we identified and verified RBBP7 as a molecular biomarker for BKVN diagnosis, which demonstrated great distinguishing ability with allograft rejection and would support clinical decision-making.

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Identification of retinoblastoma binding protein 7 (Rbbp7) as a mediator against tau acetylation and subsequent neuronal loss in Alzheimer’s disease and related tauopathies

Cited by 17 publications

References 60 publications

ZNF384: A Potential Therapeutic Target for Psoriasis and Alzheimer’s Disease Through Inflammation and Metabolism

ZNF384: A Potential Therapeutic Target for Psoriasis and Alzheimer’s Disease Through Inflammation and Metabolism

Glyphosate infiltrates the brain and increases pro-inflammatory cytokine TNFα: implications for neurodegenerative disorders

Identifying RBBP7 as a Promising Diagnostic Biomarker for BK Virus-Associated Nephropathy

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