Immunohistochemical study of the hnRNP A2 and B1 in the hippocampal formations of brains with Alzheimer's disease

Mizukami, Katsuyoshi; Ishikawa, Masanori; Iwakiri, Masahiko; Ikonomović, Miloš D.; DeKosky, Steven T.; Kamma, Hiroshi; Asada, Takashi

doi:10.1016/j.neulet.2005.05.070

Cited by 25 publications

(23 citation statements)

References 20 publications

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“…Since both nELAVs, that are well-known ARE-binding proteins, and miR-16, which contains the UAAAU complementary sequence, recognize these cis-regulatory elements, possible competition for binding to the same ARE sequences may be suggested. Moreover, given that, besides miR-15/107 miRNAs, both nELAVs and hnRNPA2/B1 RBPs were also shown to display altered expression in AD brains [44,45], we hypothesize that deregulation of post-transcriptional control of CDK5R1 expression might constitute a pathomechanism in AD.…”

Section: Discussionmentioning

confidence: 94%

The miR-15/107 Family of microRNA Genes Regulates CDK5R1/p35 with Implications for Alzheimer’s Disease Pathogenesis

et al. 2016

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Cyclin-dependent kinase 5 regulatory subunit 1 (CDK5R1) encodes p35, the main activatory subunit of cyclin-dependent kinase 5 (CDK5). The p35/CDK5 active complex plays a fundamental role in brain development and functioning, but its deregulated activity has also been implicated in various neurodegenerative disorders, including Alzheimer's disease (AD). CDK5R1 displays a large and highly evolutionarily conserved 3′-untranslated region (3′-UTR), a fact that has suggested a role for this region in the post-transcriptional control of CDK5R1 expression. Our group has recently demonstrated that two miRNAs, miR-103 and miR-107, regulate CDK5R1 expression and affect the levels of p35. MiR-103 and miR-107 belong to the miR-15/ 107 family, a group of evolutionarily conserved miRNAs highly expressed in human cerebral cortex. In this work, we tested the hypothesis that other members of this group of miRNAs, in addition to miR-103 and miR-107, were able to modulate CDK5R1 expression. We provide evidence that several miRNAs belonging to the miR-15/107 family regulate p35 levels. BACE1 expression levels were also found to be modulated by different members of this family. Furthermore, overexpression of these miRNAs led to reduced APP phosphorylation levels at the CDK5-specific Thr668 residue. We also show that miR-15/107 miRNAs display reduced expression levels in hippocampus and temporal cortex, but not in cerebellum, of AD brains. Moreover, increased CDK5R1 mRNA levels were observed in AD hippocampus tissues. Our results suggest that the downregulation of the miR-15/ 107 family might have a role in the pathogenesis of AD by increasing the levels of CDK5R1/p35 and consequently enhancing CDK5 activity.

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Section: Discussionmentioning

confidence: 94%

The miR-15/107 Family of microRNA Genes Regulates CDK5R1/p35 with Implications for Alzheimer’s Disease Pathogenesis

et al. 2016

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“…This possibility is supported by the evidence reported by Mizukami in which the most intense immunoreactivity of hnRNP A2, another number of hnRNP splicing factor family, was observed in the hippocampal CA1 region neurons in the mildly affected AD subjects (Braak stages I and II), while a decreased alteration of its immunoreactivity was observed in the moderately (Braak stages III and IV) and severely affected AD subjects (Braak stages V and VI) (Mizukami et al . ). Whether the expression of hnRNP A1 in the PBMCs increased at the early mild stage and decreased at the moderate or severe stage of AD needs further investigation.…”

Section: Discussionmentioning

confidence: 97%

“…Two nuclear RNA-binding protein families, heterogeneous nuclear ribonucleoproteins (hnRNPs) and serine/argininerich proteins (SR), play pivotal roles in regulation of alternative splicing (Busch and Hertel 2012). Both may exert antagonistic effects on selection of alternative exons, depending on their intracellular concentration or activity (Mayeda et al 1993;Zahler et al 2004;Mizukami et al 2005;Chen and Manley 2009;Guo et al 2012;Corbo et al 2013).…”

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confidence: 99%

Regulation of RAGE splicing by hnRNP A1 and Tra2β‐1 and its potential role in AD pathogenesis

Liu

et al. 2015

Journal of Neurochemistry

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The receptor for advanced glycation end products (RAGE) gene expresses two major alternative splicing isoforms, full-length membrane-bound RAGE (mRAGE) and secretory RAGE (esRAGE). Both isoforms play important roles in Alzheimer's disease (AD) pathogenesis, either via interaction of mRAGE with β-amyloid peptide (Aβ) or inhibition of the mRAGE-activated signaling pathway. In the present study, we showed that heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) and Transformer2β-1 (Tra2β-1) were involved in the alternative splicing of mRAGE and esRAGE. Functionally, two factors had an antagonistic effect on the regulation. Glucose deprivation induced an increased ratio of mRAGE/esRAGE via up-regulation of hnRNP A1 and down-regulation of Tra2β-1. Moreover, the ratios of mRAGE/esRAGE and hnRNP A1/Tra2β-1 were increased in peripheral blood mononuclear cells from AD patients. The results provide a molecular basis for altered splicing of mRAGE and esRAGE in AD pathogenesis. The receptor for advanced glycation end products (RAGE) gene expresses two major alternative splicing isoforms, membrane-bound RAGE (mRAGE) and secretory RAGE (esRAGE). Both isoforms play important roles in Alzheimer's disease (AD) pathogenesis. Mechanism for imbalanced expression of these two isoforms in AD brain remains elusive. We proposed here a hypothetic model to illustrate that impaired glucose metabolism in AD brain may increase the expression of splicing protein hnRNP A1 and reduce Tra2β-1, which cause the imbalanced expression of mRAGE and esRAGE.

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“…hnRNP B1 has two tandem repeats of RNA recognition motifs and a glycine-rich domain relevant to protein-protein interaction and RNA-protein interaction. Previous studies have suggested that hnRNP A2/B1 displayed a different response to Alzheimer's disease pathology (Ishikawa et al 2004;Mizukami et al 2005). Molecular evidence for the involvement of hnRNP A2/B1 in cerebral I/R injury will be required for a better understanding of their differential biological actions.…”

Section: Discussionmentioning

confidence: 99%

Histochemical Mapping of hnRNP A2/B1 in Rat Brain After Ischemia–Reperfusion Insults

Liu

Gao

et al. 2010

J Histochem Cytochem.

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Cerebral ischemia-reperfusion (I/R) insults result in neuronal cell death, brain tissue loss, and severe neurological deficits. However, the underlying mechanism is still not fully understood. Heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1 belongs to a family of RNA-binding proteins that plays a central role in pre-mRNA processing. Recent studies have revealed that hnRNP A2/B1 may be involved in the progress of I/R; therefore, the present study aimed to examine expression patterns of hnRNP A2/B1 to better understand posttranscriptional regulations in cerebral I/R insults. Focal cerebral I/R models were induced by right middle cerebral artery occlusion (MCAO) for 120 min followed by 3, 6, 12, 24, 48, and 72 hr of reperfusion in male Sprague-Dawley rats. We employed immunohistochemistry to examine expression of hnRNP A2/B1 in rat cerebral cortex (including cingulate cortex, striate cortex, temporal cortex, and piriform cortex) and hippocampus after I/R insults. Results showed that expression of hnRNP A2/B1 was significantly downregulated in cerebral cortex and hippocampus from 3 to 24 hr of reperfusion after MCAO for 120 min, but significantly upregulated at 48 hr of reperfusion. Unexpectedly, translocation of hnRNP A2/B1 from nucleus to cytoplasm and even to neurites was observed in cerebral cortex at 3 hr of reperfusion, reaching a peak at 24 hr of reperfusion, but not in hippocampus, indicating different posttranscriptional regulation patterns in different brain regions. Interestingly, translocation of hnRNP A2/B1 was only observed in cerebral cortex with MCAO but not in the opposite side, suggesting an I/R-specific expression pattern in the brain. Our data suggest that hnRNP A2/B1 participates in posttranscriptional regulation of neurons in cerebral cortex and hippocampus that suffered I/R insults, although posttranscriptional regulation is more extensive in neuronal cells of cerebral cortex than in hippocampus.

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Immunohistochemical study of the hnRNP A2 and B1 in the hippocampal formations of brains with Alzheimer's disease

Cited by 25 publications

References 20 publications

The miR-15/107 Family of microRNA Genes Regulates CDK5R1/p35 with Implications for Alzheimer’s Disease Pathogenesis

The miR-15/107 Family of microRNA Genes Regulates CDK5R1/p35 with Implications for Alzheimer’s Disease Pathogenesis

Regulation of RAGE splicing by hnRNP A1 and Tra2β‐1 and its potential role in AD pathogenesis

Histochemical Mapping of hnRNP A2/B1 in Rat Brain After Ischemia–Reperfusion Insults

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