scholarly journals Analysis of the role of Purα in the pathogenesis of Alzheimer's disease based on RNA-seq and ChIP-seq

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Xiaoguang Shi ◽  
Shuanglai Ren ◽  
Bingying Zhang ◽  
Shanshan Guo ◽  
Wenxin He ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Expression Profiles ◽  
Protein A ◽  
Rna Seq ◽  
Ht22 Cells ◽  
Rna Translation ◽  
Dna And Rna ◽  
Element Binding Protein ◽  
On Chip

AbstractPurine rich element binding protein A (Purα), encoded by the Purα gene, is an important transcriptional regulator that binds to DNA and RNA and is involved in processes such as DNA replication and RNA translation. Purα also plays an important role in the nervous system. To identify the function of Pura, we performed RNA sequence (RNA-seq) analysis of Purɑ-KO mouse hippocampal neuron cell line (HT22) to analyze the effect of Purα deletion on neuronal expression profiles. And combined with ChIP-seq analysis to explore the mechanism of Purα on gene regulation. In the end, totaly 656 differentially expressed genes between HT22 and Purα-KO HT22 cells have been found, which include 7 Alzheimer’s disease (AD)-related genes and 5 Aβ clearance related genes. 47 genes were regulated by Purα directly, the evidence based on CHIP-seq, which include Insr, Mapt, Vldlr, Jag1, etc. Our study provides the important informations of Purα in neuro-development. The possible regulative effects of Purα on AD-related genes consist inthe direct and indirect pathways of Purα in the pathogenesis of AD.

scholarly journals Pur-alpha participates in the progression of Alzheimer's disease through direct and indirect ways

2020 ◽  
Author(s):  
Xiaoguang Shi ◽  
Shuanglai Ren ◽  
Bingying Zhang ◽  
Shanshan Guo ◽  
Wenxin He ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuronal Development ◽  
Expression Profiles ◽  
Protein A ◽  
Notch Pathway ◽  
Neuronal Cell ◽  
Relevant Evidence ◽  
Dna And Rna ◽  
Direct Regulation

Abstract Background: Purine rich element binding protein A (Pur-alpha), encoded by the PURA gene, is an important transcriptional regulator that binds to DNA and RNA and is involved in processes such as DNA replication and RNA translation. Pur-alpha plays an important role in the nervous system. Our previous research found that the regulatory effect of Pur-alpha on APP suggests that it may be involved in the production of beta-amyloids. Suggestting that Pur-alpha may plays a role in Alzheimer ’s disease (AD), but the relevant evidence is insufficient.Methods: We performed RNA-sequencing (RNA-seq) analysis of Pura-KO mouse hippocampal neuronal cell line (HT22) to analyze the effect of puralpha deletion on neuron expression profile. And then combined with ChIP-seq analysis to explore the mechanism of Pura on gene regulation.Results: we found 656 differentially expressed genes between HT22 and Pura-KO HT22. A total of 62 overlapping genes were found by comparison with early brain protein expression profiles in mice, which may play important role in early neuronal development. We found that 7 Alzheimer’s disease (AD)-related genes (Lpl, Mapt, Mme, Ndufa3, Lrp1, Gapdh, mt-Co3) and 5 Aβ clearance related genes (Mme, C3, Lrp1, Insr, Trem2) were regulated by Pur-alpha, suggesting that Pur-alpha plays an important role in AD. Through ChIP-seq analysis, we found that Pur-alpha binds directly to 47 genes and regulates their transcription,ncluding Insr, Mapt, Vldlr, Jag1, etc. The direct regulation of Vldlr, the Reelin ligand, suggests that Pur-alpha may be involved in the process of synaptic plasticity. The direct regulation of Jag1 suggests that Pur-alpha may be involved in the Notch pathway.Conclusions: Our study re-confirms the important role of Pur-alpha in neurodevelopment. The regulation of Pur-alpha on AD-related genes means that Pur-alpha plays an important role in the pathogenesis of AD.

scholarly journals Pur-alpha participates in the progression of Alzheimer's disease through direct and indirect ways

2020 ◽  
Author(s):  
Xiaoguang Shi ◽  
Shuanglai Ren ◽  
Bingying Zhang ◽  
Shanshan Guo ◽  
Wenxin He ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuronal Development ◽  
Expression Profiles ◽  
Protein A ◽  
Neuronal Cell ◽  
Relevant Evidence ◽  
Dna And Rna ◽  
Protein Expression Profiles ◽  
Direct Regulation

Abstract Background: Purine rich element binding protein A (Pur-alpha)，encoded by the PURA gene， is an important transcriptional regulator that binds to DNA and RNA and is involved in processes such as DNA replication and RNA translation. Pur-alpha plays an important role in the nervous system. Our previous research found that the regulatory effect of Pur-alpha on APP suggests that it may be involved in the production of beta-amyloids. Suggestting that Pur-alpha may plays a role in Alzheimer ’s disease (AD), but the relevant evidence is insufficient.Methods: We performed RNA-sequencing (RNA-seq) analysis of Pura-KO mouse hippocampal neuronal cell line (HT22) to analyze the effect of puralpha deletion on neuron expression profile. And then combined with ChIP-seq analysis to explore the mechanism of Pura on gene regulation.Results: we found 656 differentially expressed genes between HT22 and Pura-KO HT22. A total of 62 overlapping genes were found by comparison with early brain protein expression profiles in mice, which may play important role in early neuronal development. We found 7 Alzheimer’s disease (AD)-related genes (Lpl, Mapt, Mme, Ndufa3, Lrp1, Gapdh, mt-Co3) and 5 Ab clearance related genes (Mme, C3, Lrp1, Insr, Trem2) were regulated by Pur-alpha, suggesting that Pur-alpha plays an important role in AD. Through ChIP-seq analysis, we found that Pur-alpha binds directly to 47 genes and regulates their transcription, including Insr, Mapt, Vldlr, Jag1, etc. The direct regulation of Vldlr，the Reelin ligand，suggests that Pur-alpha may be involved in the process of synaptic plasticity. The direct regulation of Jag1 suggests that Pur-alpha may be involved in the Notch pathway.Conclusions: Our study re-confirms the important role of Pur-alpha in neurodevelopment. The regulation of Pur-alpha on AD-related genes means that Pur-alpha plays an important role in the pathogenesis of AD.

scholarly journals GSAP regulates mitochondrial function through the Mitochondria-associated ER membrane in the pathogenesis of Alzheimer’s disease

2020 ◽  
Author(s):  
Peng Xu ◽  
Jerry C. Chang ◽  
Xiaopu Zhou ◽  
Wei Wang ◽  
Michael Bamkole ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Function ◽  
Protein A ◽  
Transcript Level ◽  
Rna Seq ◽  
Single Nucleotide ◽  
Amyloidogenic Processing ◽  
App Trafficking ◽  
Lipid Environment

ABSTRACTBiochemical, pathogenic and human genetic data confirm that GSAP (γ-secretase activating protein), a selective γ-secretase modulatory protein, plays important roles in Alzheimer’s disease (AD) and Down syndrome. However, the molecular mechanism(s) underlying GSAP-dependent pathogenesis remains largely elusive. Here, through unbiased proteomics and single-nuclei RNA-seq, we identified that GSAP regulates multiple biological pathways, including protein phosphorylation, trafficking, lipid metabolism, and mitochondrial function. We demonstrated that GSAP physically interacts with Fe65:APP complex to regulate APP trafficking/partitioning. GSAP is enriched in the mitochondria-associated membrane (MAM) and regulates lipid homeostasis through the amyloidogenic processing of APP. GSAP deletion generates a lipid environment unfavorable for AD pathogenesis, leading to improved mitochondrial function and the rescue of cognitive deficits in an AD mouse model. Finally, we identified a novel GSAP single-nucleotide polymorphism that regulates its brain transcript level and is associated with an increased AD risk. Together, our findings indicate that GSAP impairs mitochondrial function through its MAM localization, and lowering GSAP expression reduces pathological effects associated with AD.

Proteolytic processing of the amyloid-beta protein precursor of Alzheimer's disease

2002 ◽  
Vol 38 ◽  
pp. 37-49 ◽  
Author(s):  
Janelle Nunan ◽  
David H Small
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Alternative Pathway ◽  
Protein A ◽  
Proteolytic Processing ◽  
Gamma Secretase ◽  
Amyloid Beta Protein ◽  
Protein Precursor ◽  
Amyloid Beta Protein Precursor

The proteolytic processing of the amyloid-beta protein precursor plays a key role in the development of Alzheimer's disease. Cleavage of the amyloid-beta protein precursor may occur via two pathways, both of which involve the action of proteases called secretases. One pathway, involving beta- and gamma-secretase, liberates amyloid-beta protein, a protein associated with the neurodegeneration seen in Alzheimer's disease. The alternative pathway, involving alpha-secretase, precludes amyloid-beta protein formation. In this review, we describe the progress that has been made in identifying the secretases and their potential as therapeutic targets in the treatment or prevention of Alzheimer's disease.

scholarly journals Role of the lncRNA BACE1-AS in shared disease mechanisms between heart failure and Alzheimer's disease

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S Greco ◽  
A Made' ◽  
A.S Tascini ◽  
J Garcia Manteiga ◽  
S Castelvecchio ◽  
...  
Keyword(s):  
Heart Failure ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
In Situ Hybridization ◽  
Cell Apoptosis ◽  
Common Disease ◽  
Funding Source ◽  
Mrna Levels ◽  
Rna Seq

Abstract Background BACE1 encodes for β-secretase, the key enzyme involved in β-amyloid (βA) generation, a peptide well known for its involvement in Alzheimer's disease (AD). Of note, heart failure (HF) and AD share several risk factors and effectors. We recently showed that, in the heart of ischemic HF patients, the levels of both BACE1, its antisense RNA BACE1-AS and βA are all increased. BACE1-AS positively regulates the expression of BACE1, triggering βA intracellular accumulation, and its overexpression or βA administration induce cardiovascular-cell apoptosis. Aim To characterize the transcripts of the BACE1 locus and to investigate the molecular mechanisms underpinning BACE1-AS regulation of cell vitality. Methods By PCR and sequencing, we studied in the heart the expression of a variety of antisense BACE1 transcripts predicted by FANTOM CAT Epigenome. We studied BACE1 RNA stability by BrdU pulse chase experiments (BRIC assay). The cellular localization of BACE1-AS RNA was investigated by in situ hybridization assay. BACE1-AS binding RNAs were evaluated by BACE1-AS-MS2-Tag pull-down in AC16 cardiomyocytes followed by RNA-seq. Enriched RNAs were validated by qPCR and analysed by bioinformatics comparison with publicly available gene expression datasets of AD brains. Results We readily detected several antisense BACE1 transcripts expressed in AC16 cardiomyocytes; however, only BACE1-AS RNAs overlapping exon 6 of BACE1 positively regulated BACE1 mRNA levels, acting by increasing its stability. BACE1 silencing reverted cell apoptosis induced by BACE1-AS expression, indicating that BACE1 is a functional target of BACE1-AS. However, in situ hybridization experiments indicated a mainly nuclear localization for BACE1-AS, which displayed a punctuated distribution, compatible with chromatin association and indicative of potential additional targets. To identify other BACE1-AS binding RNAs, a BACE1-AS-MS2-tag pull-down was performed and RNA-seq of the enriched RNAs identified 698 BACE1-AS interacting RNAs in cardiomyocytes. Gene ontology of the BACE1-AS binding RNAs identified categories of relevance for cardiovascular or neurological diseases, such as dopaminergic synapse, glutamatergic synapse, calcium signalling pathway and voltage-gated channel activity. In spite of the differences between brain and heart transcriptomes, BACE1-AS-interacting RNAs identified in cardiomyocytes were significantly enriched in transcripts differentially expressed in AD brains as well as in RNAs expressed by enhancer genomic regions that are significantly hypomethylated in AD brains. Conclusions These data shed a new light on the complexity of BACE1-AS locus and on the existence of RNAs interacting with BACE1-AS with a potential as enhancer-RNAs. Moreover, the dysregulation of the BACE1-AS/BACE1/βA pathway may be a common disease mechanism shared by cardiovascular and neurological degenerative diseases. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Italian Health Ministery_Ricerca Corrente 2020

scholarly journals A new non-aggregative splicing isoform of human Tau is decreased in Alzheimer’s disease

2021 ◽  
Author(s):  
Vega García-Escudero ◽  
Daniel Ruiz-Gabarre ◽  
Ricardo Gargini ◽  
Mar Pérez ◽  
Esther García ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuroblastoma Cells ◽  
Rna Seq ◽  
Human Neuroblastoma Cells ◽  
Human Neuroblastoma ◽  
Post Translational Modifications ◽  
Protein Levels ◽  
Tau Isoform ◽  
Human Specific

AbstractTauopathies, including Alzheimer’s disease (AD) and frontotemporal lobar degeneration with Tau pathology (FTLD-tau), are a group of neurodegenerative disorders characterized by Tau hyperphosphorylation. Post-translational modifications of Tau such as phosphorylation and truncation have been demonstrated to be an essential step in the molecular pathogenesis of these tauopathies. In this work, we demonstrate the existence of a new, human-specific truncated form of Tau generated by intron 12 retention in human neuroblastoma cells and, to a higher extent, in human RNA brain samples, using qPCR and further confirming the results on a larger database of human RNA-seq samples. Diminished protein levels of this new Tau isoform are found by Westernblotting in Alzheimer’s patients’ brains (Braak I n = 3; Braak II n = 6, Braak III n = 3, Braak IV n = 1, and Braak V n = 10, Braak VI n = 8) with respect to non-demented control subjects (n = 9), suggesting that the lack of this truncated isoform may play an important role in the pathology. This new Tau isoform exhibits similar post-transcriptional modifications by phosphorylation and affinity for microtubule binding, but more interestingly, is less prone to aggregate than other Tau isoforms. Finally, we present evidence suggesting this new Tau isoform could be linked to the inhibition of GSK3β, which would mediate intron 12 retention by modulating the serine/arginine rich splicing factor 2 (SRSF2). Our results show the existence of an important new isoform of Tau and suggest that further research on this less aggregation-prone Tau may help to develop future therapies for Alzheimer’s disease and other tauopathies.

Comprehensive Analysis of Differential Expression Profiles of Long Non-coding RNAs with Associated Co-expression and Competing Endogenous RNA Networks in the Hippocampus of Patients with Alzheimer's Disease

2021 ◽  
Vol 18 ◽  
Author(s):  
Jian-Jun Zhang ◽  
Ze-Xuan-Zhu ◽  
Guang-Min-Xu ◽  
Peng Su ◽  
Qian Lei ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Expression Profiles ◽  
Gene Expression Omnibus ◽  
Competing Endogenous Rna ◽  
Pathogenic Genes ◽  
Non Coding Rna ◽  
Using Data ◽  
Trans Regulation

Background: Alzheimer's disease (AD) is still one of the major threats to human health. Although a satisfactory treatment for AD has not yet been discovered, it is necessary to continue to search for novel approaches to deal with this insidious and debilitating disease. Although numerous studies have shown that long non-coding RNA (lncRNA) occupy a significant role in a variety of diseases, their roles in AD remain unclear. Objectives: Using data analysis to explore the role of lncRNA in the course of AD, to further our understanding of AD, and to look forward to finding a new breakthrough for the treatment of AD. Methods: We downloaded and screened expression data of the hippocampal regions of patients with AD from the Gene Expression Omnibus database. We generated lncRNA-miRNA-mRNA networks based on the competing endogenous RNA (ceRNA) hypothesis, and according to gene expression level, we constructed a coding-noncoding co-expression (CNC) network and then executed cis- and trans-regulation analyses. Results: Through comprehensive and systematic analyses, we found that lncRNAs MALAT1, OIP5-AS1, LINC00657, and lnc-NUMB-1 regulated the expression of the key AD pathogenic genes APP, PSEN1, BACE1; and that these lncRNAs may promote the distribution of β-amyloid (Aβ protein) in the brain through exosomes. In addition, lncRNAs were found to adjust viral transcriptional expression, thereby further supporting viral pathogenesis for AD. Conclusions: The lncRNAs MALAT1, OIP5-AS1, LINC00657, and lnc-NUMB-1 that are present in the hippocampus of AD patients exert an important influence on the development of this disease.

scholarly journals E22Δ Mutation in Amyloidβ-Protein Promotesβ-Sheet Transformation, Radical Production, and Synaptotoxicity, But Not Neurotoxicity

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Takayuki Suzuki ◽  
Kazuma Murakami ◽  
Naotaka Izuo ◽  
Toshiaki Kume ◽  
Akinori Akaike ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Conformational Change ◽  
Deletion Mutant ◽  
Protein A ◽  
Type A ◽  
Synaptic Dysfunction ◽  
Wild Type ◽  
Radical Production

Oligomers of 40- or 42-mer amyloidβ-protein (Aβ40, Aβ42) cause cognitive decline and synaptic dysfunction in Alzheimer's disease. We proposed the importance of a turn at Glu22 and Asp23 of Aβ42 to induce its neurotoxicity through the formation of radicals. Recently, a novel deletion mutant at Glu22 (E22Δ) of Aβ42 was reported to accelerate oligomerization and synaptotoxicity. To investigate this mechanism, the effects of the E22Δ mutation in Aβ42 and Aβ40 on the transformation ofβ-sheets, radical production, and neurotoxicity were examined. Both mutants promotedβ-sheet transformation and the formation of radicals, while their neurotoxicity was negative. In contrast, E22P-Aβ42 with a turn at Glu22 and Asp23 exhibited potent neurotoxicity along with the ability to form radicals and potent synaptotoxicity. These data suggest that conformational change in E22Δ-Aβis similar to that in E22P-Aβ42 but not the same, since E22Δ-Aβ42 exhibited no cytotoxicity, unlike E22P-Aβ42 and wild-type Aβ42.

scholarly journals Formation of Toxic Amyloid Fibrils by Amyloidβ-Protein on Ganglioside Clusters

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Katsumi Matsuzaki
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Physicochemical Properties ◽  
Lipid Rafts ◽  
Molecular Mechanisms ◽  
Amyloid Fibrils ◽  
Protein A ◽  
Pivotal Role ◽  
Membrane Interaction

It is widely accepted that the conversion of the soluble, nontoxic amyloidβ-protein (Aβ) monomer to aggregated toxic Aβrich inβ-sheet structures is central to the development of Alzheimer’s disease. However, the mechanism of the abnormal aggregation of Aβin vivo is not well understood. Accumulating evidence suggests that lipid rafts (microdomains) in membranes mainly composed of sphingolipids (gangliosides and sphingomyelin) and cholesterol play a pivotal role in this process. This paper summarizes the molecular mechanisms by which Aβaggregates on membranes containing ganglioside clusters, forming amyloid fibrils. Notably, the toxicity and physicochemical properties of the fibrils are different from those of Aβamyloids formed in solution. Furthermore, differences between Aβ-(1–40) and Aβ-(1–42) in membrane interaction and amyloidogenesis are also emphasized.

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