Altered Machinery of Protein Synthesis in Alzheimer's: From the Nucleolus to the Ribosome
Open accessAbstract
Ribosomes and protein synthesis have been reported to be altered in the cerebral cortex at advanced stages of Alzheimer's disease (AD). Modifications in the hippocampus with disease progression have not been assessed. Sixty‐seven cases including middle‐aged (MA) and AD stages I–VI were analyzed. Nucleolar chaperones nucleolin, nucleophosmin and nucleoplasmin 3, and upstream binding transcription factor RNA polymerase I gene ( UBTF ) mRNAs are abnormally regulated and their protein levels reduced in AD. Histone modifications dimethylated histone H3K9 (H3K9me2) and acetylated histone H3K12 (H3K12ac) are decreased in CA1. Nuclear tau declines in CA1 and dentate gyrus (DG), and practically disappears in neurons with neurofibrillary tangles. Subunit 28 ribosomal RNA (28S rRNA) expression is altered in CA1 and DG in AD. Several genes encoding ribosomal proteins are abnormally regulated and protein levels of translation initiation factors eIF2α, eIF3η and eIF5, and elongation factor eEF2, are altered in the CA1 region in AD. These findings show alterations in the protein synthesis machinery in AD involving the nucleolus, nucleus and ribosomes in the hippocampus in AD some of them starting at first stages (I–II) preceding neuron loss. These changes may lie behind reduced numbers of dendritic branches and reduced synapses of CA1 and DG neurons which cause hippocampal atrophy.
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TL;DR
This study analyzed 67 cases including middle-aged (MA) and Alzheimer’s disease (AD) stages I–VI and reports altered protein synthesis machinery from nucleolus to ribosome in the hippocampus. Some changes appear at stages I–II, before neuron loss, and may contribute to reduced dendritic branches, synapse loss, and hippocampal atrophy.
Key findings
- Nucleolar chaperones NCL, NPM1, NPM3 and UBTF mRNAs are abnormally regulated and their protein levels reduced in AD. In CA1, UBTF mRNA is down-regulated at stages I–II, III–IV and V–VI; NPM1 is up-regulated at I–II and III–IV but normal at V–VI; NPM3 is up-regulated at III–IV and down-regulated at V–VI. In DG, NPM1, NPM3 and UBTF mRNAs are reduced at V–VI. Immunoreactivity for NPM1, NPM3, NCL and UBF decreases in CA1 and DG with disease progression.
- Histone modifications H3K9me2 and H4K12ac decline in CA1 and DG neurons with AD progression. Nuclear tau-100 immunoreactivity decreases in CA1 and DG and practically disappears in neurons with neurofibrillary tangles.
- 28S rRNA is altered: in CA1 it is down-regulated at AD I–II and III–IV but up-regulated at V–VI; in DG it is transiently down-regulated at III–IV. 18S rRNA is not significantly altered in either region.
- Ribosomal protein mRNAs are altered: 11 of 16 examined in CA1 and 9 of 16 in DG at stage V–VI. Some changes occur at I–II, including down-regulation of RPL23A, RPL26, RPL31, RPS5, RPS6, RPS10 and RPS13 in DG, and up-regulation of RPL5/RPL26 with down-regulation of RPS5/RPS6 in CA1. In CA1, eIF2α protein increases at III–IV and V–VI, eIF3η decreases at the same stages, eIF5 is slightly reduced only at III–IV, eEF2 is reduced only at I–II, and eEF1A is unchanged.
Methods
- Post-mortem brain samples from 67 cases: 18 MA and AD cases at Braak stages I–II (n = 16), III–IV (n = 16) and V–VI (n = 17). CA1 and dentate gyrus (DG) were examined in parallel; AD diagnosis followed Braak and Braak staging.
- TaqMan PCR measured mRNAs for nucleolar genes, rRNA and ribosomal proteins; immunohistochemistry and cell counting assessed nucleolar proteins, histones and nuclear tau; Western blotting in CA1 assessed initiation factors eIF2α, eIF3η, eIF5 and elongation factors eEF1A, eEF2.
- Statistical analyses used Student t-test for TaqMan data and one-way ANOVA followed by Tukey’s post hoc test for cell counting and Western blotting, with significance at *P < 0.05, P < 0.01, *P < 0.001.
Limitations
- The paper states that none of the alterations proves protein synthesis is impaired; attempts to measure protein synthesis by labeled amino acid incorporation in post-mortem human brain were unsuccessful due to very low and erratic S35 methionine incorporation. The small size of the DG prevented use of frozen samples for protein studies of translation factors.
- The paper notes that regional vulnerability differences between CA1 and DG remain unresolved.
- Evident from the text: findings rely on post-mortem human tissue, some assays used subsets of cases (TaqMan PCR: 14 controls and 28 AD cases; cell counting: four to six cases per group), and mRNA and protein levels did not always match, which the authors suggest may involve epigenetic factors and non-coding RNAs.
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Claims the paper makes
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- Findingown data§ Results
Decreased eIF3η protein expression occurs in CA1 at AD stages III-IV and V-VI.
“whereas decreased expression of eIF3η occurred in parallel at the same stages of AD.”
Quote in the paperSubstantial claim - Findingown data§ Results
In the CA1 region of AD cases at stages III-IV, NPM3 mRNA is up-regulated compared with MA.
“In addition, NPM3 mRNA was up‐regulated at stages III–IV (Table 1).”
Quote in the paperNot a substantial claim - Findingown data§ Results
In CA1, 18S rRNA is not modified at any AD stage.
“Regarding CA1, no modifications in 18S rRNA expression levels were found at any stage”
Quote in the paperNot a substantial claim - Findingown data§ Results
No immunohistochemical differences in NPM1, NPM3, NCL, and UBF are seen between MA and AD stages I-II in DG and CA1.
“Importantly, no immunohischemical differences regarding NPM1, NPM3, NCL and UBF were seen between MA individuals and AD cases at stages I–II in DG and CA1.”
Quote in the paperSubstantial claim - Findingown data§ Results
Nuclear tau-100 immunoreactivity decreases in CA1, DG, hilus, entorhinal cortex, and temporal cortex with AD progression.
“Decreased tau‐100 nuclear immunoreactivity was observed in all these regions in AD with disease progression.”
Quote in the paperSubstantial claim
- Findingown data§ Results
NPM3 immunoreactivity progressively fades in the nucleolus of CA1 and DG neurons with AD progression.
“NPM3 immunoreactivity progressively faded in the nucleolus of CA1 and DG neurons with disease progression”
Quote in the paperSubstantial claim - Findingown data§ Results
18S rRNA is not significantly altered in the DG in AD compared with MA.
“Subunit 18 ribosomal RNA (18S rRNA) was not significantly altered in the DG in AD when compared with MA cases.”
Quote in the paperNot a substantial claim - Findingown data§ Results
A slight reduction in eIF5 is found in CA1 only at AD stages III-IV.
“A slight reduction in eIF5 was found only at stages III–IV (Figure 5A).”
Quote in the paperNot a substantial claim - Findingown data§ Results
No modifications in eEF1A expression levels are noted in CA1 with AD progression.
“No modifications in the expression levels of eEF1A were noted with disease progression (Figure 5B).”
Quote in the paperNot a substantial claim - Findingown data§ Discussion
Reduced NPM1, NPM3, NCL and UBF protein levels are seen in CA1 at stages III-IV.
“Reduced NPM1, NPM3, NCL and UBF protein levels are seen in CA1 at stages III–IV (Tables 1 and 2).”
Quote in the paperSubstantial claim - Findingown data§ Results
Total disappearance of tau-100 in the nucleus parallels cytoplasmic tau accumulation in NFTs.
“only total disappearance of tau‐100 in the nucleus paralleled cytoplasmic tau accumulation in NFTs”
Quote in the paperSubstantial claim - Findingown data§ Results
28S rRNA is down-regulated in the DG in AD stages III-IV compared with MA.
“However, subunit 28 ribosomal RNA (28S rRNA) was down‐regulated in the DG in AD stages III‐IV in relation to MA cases.”
Quote in the paperSubstantial claim - Findingown data§ Results
H3K9me2 and H4K12ac staining decline in CA1 and DG neurons with AD progression.
“H3K9me2 (Figure 3A–D) and H4K12ac (Figure 3E–H) staining declined in CA1 and DG neurons with disease progression (Table 2).”
Quote in the paperSubstantial claim - Findingown data§ Discussion
Altered NPM1 and UBTF gene expression is already observed in CA1 at stages I-II.
“Importantly, altered NPM1 and UBTF gene expression is already observed in CA1 at stages I–II.”
Quote in the paperSubstantial claim - Findingown data§ Results
Quantification shows significant decrease in NPM1, NPM3, NCL, and UBF immunoreactivity in CA1 and DG with AD progression.
“quantification of stained nuclei with antibodies anti‐NPM1, NPM3, NCL and UBF revealed a significant decrease (ranging from P < 0.05 to P < 0.001) in the immunoreactivity of all these markers in CA1 and DG with AD progression.”
Quote in the paperSubstantial claim - Findingown data§ Results
Tau-100 immunoreactivity translocates to NFTs and dystrophic neurites of senile plaques in CA1, entorhinal cortex, and temporal neocortex.
“This was accompanied by translocated tau‐100 immunoreactivity to NFTs and dystrophic neurites of senile plaques in CA1, entorhinal cortex and temporal neocortex”
Quote in the paperSubstantial claim - Findingown data§ Results
Increased eIF2α protein levels are found in CA1 at AD stages III-IV and V-VI.
“Increased eIF2α protein levels were found at stages III–IV and V–VI”
Quote in the paperSubstantial claim - Findingown data§ Results
NPM1 immunoreactivity decreases in the nucleolus of CA1 neurons along AD progression, being very weak at stages V-VI.
“NPM1 immunoreactivity decreased in the nucleolus of CA1 neurons along disease progression, with the immunostaining being very weak at stages V–VI”
Quote in the paperSubstantial claim - Findingown data§ Results
H4K12ac-immunoreactive globules and bars appear in the neuropil of the hippocampus at advanced AD stages.
“Moreover, H4K12ac‐immunoreactive globules and bars in the neuropil of the hippocampus were noted at advanced stages of AD”
Quote in the paperNot a substantial claim - Findingown data§ Results
In the DG of AD cases at stages V-VI, mRNA expression of NPM1, NPM3, and UBTF is reduced compared with MA.
“significantly reduced expression of NPM1, NPM3 and UBTF mRNAs was seen in the DG of AD cases at stages V–VI (Table 1).”
Quote in the paperSubstantial claim - Findingnone given§ Discussion
In Alzheimer's disease, 28S rRNA in the CA1 region is up-regulated at Braak stages V-VI compared with middle-aged controls.
“28S rRNA in CA1 is down‐regulated at stages I–IV and up‐regulated at stages V–VI compared with MA”
Quote in the paperSubstantial claim - Findingnone given§ Discussion
In Alzheimer's disease, 28S rRNA in the CA1 region is down-regulated at Braak stages I-IV compared with middle-aged controls.
“28S rRNA in CA1 is down‐regulated at stages I–IV and up‐regulated at stages V–VI compared with MA”
Quote in the paperSubstantial claim - Findingnone given§ Discussion
Alterations of NCL, NPMs and UBF increase with disease progression in Alzheimer's disease.
“alterations of NCL, NPMs and UBF increase with disease progression”
Quote in the paperSubstantial claim - Findingnone given§ Discussion
In Alzheimer's disease, 28S rRNA in the dentate gyrus is transiently down-regulated at Braak stages III-IV.
“28S rRNA in the DG is transiently down‐regulated at stages III–IV in AD.”
Quote in the paperSubstantial claim - Findingown data§ Discussion
Nuclear tau-100 virtually disappears in neurons with neurofibrillary tangles.
“Nuclear tau‐100 virtually disappears in neurons with NFTs.”
- Also stated in: § Discussion · plain
“Eventually, nuclear tau is no longer present in neurons with NFTs.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Findingnone given§ Discussion
H3K9me2 and H4K12ac nuclear immunoreactivity declines in CA1 and DG with Alzheimer's disease progression.
“H3K9me2 and H4K12ac nuclear immunoreactivity declines in CA1 and DG with AD progression”
Quote in the paperNot a substantial claim - Findingown data§ Discussion
The present data show a marked decrease of nuclear tau-100 in CA1 and DG neurons with Alzheimer's disease progression.
“The present data illustrate a marked decrease of nuclear tau‐100 in CA1 and DG neurons with disease progression.”
Quote in the paperSubstantial claim - Findingown data§ Discussion
Three RPLs and four RPSs are down-regulated in the DG in Alzheimer's disease stages I-II of Braak and Braak.
“3 RPLs and 4 RPSs are down‐regulated in the DG”
Quote in the paperSubstantial claim - Findingown data§ Discussion
eIF3η protein levels are reduced in the CA1 region of the hippocampus in Alzheimer's disease with disease progression.
“eIF3η and eIF5 protein levels are reduced whereas eIF2α protein levels are increased in the CA1 region of the hippocampus in AD with disease progression.”
Quote in the paperSubstantial claim - Findingown data§ Discussion
eIF2α protein levels are increased in the CA1 region of the hippocampus in Alzheimer's disease with disease progression.
“eIF3η and eIF5 protein levels are reduced whereas eIF2α protein levels are increased in the CA1 region of the hippocampus in AD with disease progression.”
Quote in the paperSubstantial claim - Findingown data§ Discussion
RPL23A, RPL26, RPL31, RPS5, RPS6, RPS10 and RPS13 mRNAs are down-regulated in the DG at stages I-II.
“RPL23A, RPL26, RPL31, RPS5, RPS6, RPS10 and RPS13 mRNAs are down‐regulated in DG at stages I–II.”
Quote in the paperSubstantial claim - Findingown data§ Discussion
Two RPLs and two RPSs are up- and down-regulated, respectively, in CA1 in Alzheimer's disease stages I-II of Braak and Braak.
“two RPLs and two RPSs are up‐ and down‐regulated, respectively in CA1 in AD stages I–II of Braak and Braak.”
Quote in the paperSubstantial claim - Findingown data§ Discussion
Decreased nuclear tau is not restricted to neurons with neurofibrillary tangles.
“Moreover, decreased nuclear tau is not restricted to neurons with NFTs.”
Quote in the paperSubstantial claim - Findingown data§ Discussion
Changes in Alzheimer's disease differ in the CA1 and DG at the beginning and along disease progression.
“changes in AD differ in the CA1 and DG at the beginning and along disease progression.”
Quote in the paperSubstantial claim - Findingown data§ Discussion
eIF5 protein levels are reduced in the CA1 region of the hippocampus in Alzheimer's disease with disease progression.
“eIF3η and eIF5 protein levels are reduced whereas eIF2α protein levels are increased in the CA1 region of the hippocampus in AD with disease progression.”
Quote in the paperSubstantial claim - Findingown data§ Discussion
Nine of sixteen mRNAs encoding ribosomal proteins examined are altered in the DG in Alzheimer's disease at stage V-VI.
“and nine of sixteen in the DG at the same AD stage.”
Quote in the paperSubstantial claim - Findingown data§ Discussion
Eleven of sixteen mRNAs encoding ribosomal proteins examined are altered in CA1 in Alzheimer's disease at stage V-VI.
“Eleven of sixteen mRNAs encoding ribosomal proteins examined here are altered in CA1 in AD at stage V–VI”
Quote in the paperSubstantial claim - Interpretationown data§ Discussion
The present observations show nucleolar stress in the hippocampus, mainly in CA1 but also in DG, in AD.
“The present observations show nucleolar stress in the hippocampus, mainly in CA1 but also in DG, in AD.”
Quote in the paperSubstantial claim - Interpretationown data§ Discussion
This study shows altered mRNA expression and protein levels of crucial players in protein synthesis, from the nucleolus to the ribosomes, in the DG and CA1 region of the hippocampus of AD cases at different stages of disease progression compared with MA individuals.
“This study shows altered mRNA expression and protein levels of crucial players in the process of protein synthesis, from the nucleolus to the ribosomes, in the DG and CA1 region of the hippocampus of AD cases at different stages of disease progression when compared with MA individuals with no neurological alterations and no AD‐related pathology.”
Quote in the paperSubstantial claim - Interpretationreasoning§ Discussion
Nucleolar alterations in AD are probably not a mere consequence of cell death as altered mRNA regulation of NPM1 and UBTF first occurs before any evidence of neuron loss in the CA1 region at stages I-II.
“Therefore, nucleolar alterations in AD are probably not a mere consequence of cell death as altered mRNA regulation of NPM1 and UBTF first occurs before any evidence of neuron loss in the CA1 region of the hippocampus at stages I–II.”
Quote in the paperSubstantial claim - Interpretationown data§ Discussion
Reduced numbers of nucleoli and decreased numbers of NPM1-, NPM3-, NCL- and UBF-immunoreactive nucleoli are consistent, in part, with neuron loss at stages III-IV and V-VI.
“Reduced numbers of nucleoli as revealed with Nissl staining together with significant decreased numbers of NPM1‐, NPM3‐, NCL‐ and UBF‐immunoreactive nucleoli is consistent, in part, with neuron loss at stages III–IV and V–VI.”
Quote in the paperSubstantial claim - Interpretationown data§ Discussion
Tau accumulation in neurofibrillary tangles is only one of the terminal stages of tau metabolism disruption in Alzheimer's disease.
“tau accumulation in NFTs is only one of the terminal stages of tau metabolism disruption in AD.”
Quote in the paperSubstantial claim - Premisecitation§ Discussion
NCL and NPMs regulate rRNA transcription through the modulation of H3K9me2 and H4K12ac in rRNA genes.
“NCL and NPMs regulate rRNA transcription through the modulation of H3K9m2 and H4K12ac in rRNA genes 18, 98.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [18] 18. Cong R, Das S, Ugrinova I, Kumar S, Mongerlard F, Wong J, Bouvet P (2012) Interaction of nucleolin with ribosomal RNA genes and its role in RNA polymerase I transcription. Nucleic Acids Res 40:9441–9454. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
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Not checked in the free run.
- Interpretationreasoning§ Introduction
Together, these findings suggest a complex scenario in which several pathways, from the nucleus and nucleolus to the ribosome, are altered in the cerebral cortex in AD.
“Together, these findings suggest a complex scenario in which several pathways, from the nucleus and nucleolus to the ribosome, are altered in the cerebral cortex in AD.”
Quote in the paperSubstantial claim - Premisecitation§ Discussion
Nuclear tau induces DNA conformational changes in neural cells.
“Nuclear tau induces DNA conformational changes in neural cells 81”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [81] 81. Qu MH, Li H, Tian R, Nie CL, Liu Y Han BS, He RQ (2004) Neuronal tau induces DNA conformational changes observed by atomic force microscopy. Neuroreport 15:2723–2727. [PubMed] [Google Scholar]
Not checked in the free run.
- Interpretationcitation§ Discussion
Other factors, such as epigenetic regulation of rDNA, are probably implicated in the altered rRNA biogenesis in Alzheimer's disease.
“other factors, as epigenetic regulation of rDNA 80, are probably implicated in the altered rRNA biogenesis in AD.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [80] 80. Pietrzak M, Rempala G, Nelson PT, Zheng JJ, Hetman M (2011) Epigenetic silencing of nucleolar rRNA genes in Alzheimer's disease PLoS One 6:e22585. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- Premisecitation§ Discussion
Nuclear tau prevents DNA damage by oxidative stress.
“prevents DNA damage by oxidative stress 94, 106”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [94] 94. Sultan A, Nesslany F, Violet M, Bégard S, Loyens A, Talahari S et al (2011) Nuclear tau, a key player in neuronal DNA protection. J Biol Chem 286:4566–4575. [DOI] [PMC free article] [PubMed] [Google Scholar] source
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Not checked in the free run.
- Premisecitation§ Discussion
Oxidative damage to mRNA, tRNA and rRNA occurs in Alzheimer's disease.
“oxidative damage to mRNA, tRNA and rRNA occurs in AD”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [26] 26. Ding Q, Markesbery WR, Chen Q, Li F, N. Keller JN (2005) Ribosome dysfunction is an early event in Alzheimer's disease. J Neurosci 25:9171–9175. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [27] 27. Ding Q, Markesbery WR, Cecarini V, Keller JN (2006) Decreased RNA, and increased RNA oxidation, in ribosomes from early Alzheimer's disease. Neurochem Res 31:705–710. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [48] 48. Honda K, Smith MA, Zhu X, Baus D, Merrick WC, Tartakoff AM et al (2005) Ribosomal RNA in Alzheimer disease is oxidized by bound redox‐active iron. J Biol Chem 280:20978–20986. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- Interpretationreasoning§ Discussion
Specific post-translational modifications of selected histones involved in rRNA synthesis are altered in hippocampus neurons in Alzheimer's disease.
“thus suggesting that specific post‐translational modifications of selected histones which are involved in rRNA synthesis are altered in hippocampus neurons in AD.”
Quote in the paperSubstantial claim - Premisecitation§ Discussion
Oxidative damage to RNA may produce ribosomal dysfunction and altered protein synthesis.
“such damage may produce ribosomal dysfunction and altered protein synthesis 26, 27, 48, 75, 76, 90, 91.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [26] 26. Ding Q, Markesbery WR, Chen Q, Li F, N. Keller JN (2005) Ribosome dysfunction is an early event in Alzheimer's disease. J Neurosci 25:9171–9175. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [27] 27. Ding Q, Markesbery WR, Cecarini V, Keller JN (2006) Decreased RNA, and increased RNA oxidation, in ribosomes from early Alzheimer's disease. Neurochem Res 31:705–710. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [48] 48. Honda K, Smith MA, Zhu X, Baus D, Merrick WC, Tartakoff AM et al (2005) Ribosomal RNA in Alzheimer disease is oxidized by bound redox‐active iron. J Biol Chem 280:20978–20986. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- Premisecitation§ Discussion
Increased eIF2α correlates with increased p-eIF2α in Alzheimer's disease.
“Increased eIF2α correlates with increased p‐eIF2α in AD as previously reported 17, 34, 49, 50.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [17] 17. Chang RC, Wong AK, Ng HK, Hugon J (2002) Phosphorylation of eukaryotic initiation factor‐2alpha (eIF2alpha) is associated with neuronal degeneration in Alzheimer's disease. Neuroreport 13:2429–2432. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
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Not checked in the free run.
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Not checked in the free run.
- Interpretationreasoning§ Discussion
Altered gene expression of ribosomal proteins occurs before the appearance of cell death.
“Therefore, altered gene expression of ribosomal proteins occurs before the appearance of cell death.”
Quote in the paperSubstantial claim - Interpretationown data§ Discussion
The present findings show for the first time that multiple alterations in pathways involved in protein synthesis occur at very early stages of cases with Alzheimer's disease-related pathology, before the appearance of clinical symptoms if they would ever have appeared.
“the present findings show also for the first time that multiple alterations in pathways involved in protein synthesis occur at very early stages of cases with AD‐related pathology, before the appearance of clinical symptoms if they would ever have appeared 35.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [35] 35. Ferrer I (2012) Defining Alzheimer as a common age‐related neurodegenerative process not inevitably leading to dementia. Prog Neurobiol 97:38–51. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- Rests on an assumption: Altered expression of components of the protein synthesis machinery reflects altered protein synthesis in Alzheimer's disease.
- Premisecitation§ Discussion
Phosphorylation of eIF2 on its α subunit prevents the delivery of initiator methionyl-tRNA, resulting in global inhibition of translation of most mRNAs.
“Phosphorylation of eIF2 on its α subunit prevents the delivery of initiator methionyl‐tRNA, resulting in global inhibition of translation of most mRNAs 47.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [47] 47. Harding HP, Zhang Y, Ron D (1999) Protein translation and folding are coupled by an endoplasmic‐reticulum‐resident kinase. Nature 397:271–274. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- Study design and conductown data§ Discussion
Analysis of protein synthesis using incorporation of labeled amino acids to proteins in post-mortem human brain samples has been unsuccessful.
“analysis of protein synthesis using incorporation of labeled amino acids to proteins in post‐mortem human brain samples has been unsuccessful.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [26] 26. Ding Q, Markesbery WR, Chen Q, Li F, N. Keller JN (2005) Ribosome dysfunction is an early event in Alzheimer's disease. J Neurosci 25:9171–9175. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [27] 27. Ding Q, Markesbery WR, Cecarini V, Keller JN (2006) Decreased RNA, and increased RNA oxidation, in ribosomes from early Alzheimer's disease. Neurochem Res 31:705–710. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- Interpretationreasoning§ Discussion
Together these observations support altered protein synthesis with disease progression.
“Together these observations support altered protein synthesis with disease progression.”
Quote in the paperSubstantial claim- Rests on an assumption: Altered expression of components of the protein synthesis machinery reflects altered protein synthesis in Alzheimer's disease.
- Interpretationown data§ Discussion
The present observations may help to improve understanding of neuronal atrophy in CA1 and DG in Alzheimer's disease resulting from altered molecular machinery of protein synthesis involving specific pathways in the nucleolus, nucleus and ribosome.
“The present observations may help to improve understanding of neuronal atrophy in CA1 and DG in AD resulting from altered molecular machinery of protein synthesis involving specific pathways in the nucleolus, nucleus and ribosome.”
Quote in the paperSubstantial claim- Rests on an assumption: Altered expression of components of the protein synthesis machinery reflects altered protein synthesis in Alzheimer's disease.
- Interpretationown data§ Discussion
Decreased levels of nuclear tau precede cytoplasmic tau hyper-phosphorylation.
“Decreased levels of nuclear tau precede cytoplasmic tau hyper‐phosphorylation.”
Quote in the paperSubstantial claim - Interpretationown data§ Discussion
Not all these changes can be linked to neuronal loss as they first appear at stages in which no cell death is found in the hippocampus in Alzheimer's disease.
“not all these changes can be linked to neuronal loss as they first appear at stages in which no cell death is found in the hippocampus in AD.”
Quote in the paperSubstantial claim - Interpretationown data§ Discussion
Reduced nuclear tau is a distinct alteration of tau metabolism in Alzheimer's disease.
“Therefore, reduced nuclear tau is a distinct alteration of tau metabolism in AD.”
Quote in the paperSubstantial claim
- May combine two claims. 26
- The quote only partly states this claim. 2
- Classified as probably not a substantial claim. 17
May combine two claims.
Findingown data§ ResultsIn CA1, RPL5 and RPL26 mRNAs are up-regulated and RPS5 and RPS26 mRNAs down-regulated in AD I-II compared with MA.
“Regarding CA1, RPL5 and RPL26 mRNAs were up‐regulated and RPS5 and RPS26 mRNAs down‐regulated in AD I‐II in relation to MA cases.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ ResultsmRNA levels of several ribosomal proteins are down-regulated in the DG in AD I-II, III-IV, and V-VI, with some up-regulation at V-VI.
“mRNA levels of RPL23A, RPL26, RPL31, RPS5, RPS6, RPS10 and RPS13 were down‐regulated in the DG in AD I–II compared with MA; and mRNAs of RPL21, RPL23A, RPL27, RPS5, RPS6, RPS10, and RPS13 in AD III–IV in comparison with MA.”
- Also stated in: § Results · plain
“RPL7, RPL21, RPL26, RPL27, RPL31, RPS10, RPS16 and RPS17 mRNA levels were significantly down‐regulated and RPL22 up‐regulated in DG at stages V–VI when compared with MA cases”
Quote in the paperSubstantial claim- Also stated in: § Results · plain
May combine two claims.
Findingown data§ ResultsIn the CA1 region of AD cases at stages I-II and III-IV, NPM1 mRNA is up-regulated and UBTF mRNA is down-regulated compared with MA.
“Regarding the CA1 region, NPM1 up‐regulation and UBTF down‐regulation were observed in AD at stages I–II and III–IV when compared with MA cases.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ ResultsUBF immunoreactivity decreases in nucleolus and diffuse nucleus with AD progression, and UBF translocates to cytoplasm and integrates into NFTs but not dystrophic neurites of senile plaques.
“Nucleolar and diffuse nuclear UBF immunoreactivity decreased with AD progression (Figure 2E–L). In addition, UBF immunoreactivity translocated to the cytoplasm and was integrated into NFTs but not in dystrophic neurites of senile plaques”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ Results28S rRNA is reduced in CA1 in AD I-II and III-IV but up-regulated at AD V-VI compared with MA.
“28S rRNA was reduced in AD I–II and AD III–IV but it was found to be up‐regulated at AD stages V–VI compared with MA (Table 1).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ ResultsReduced numbers of nucleoli (Nissl) and NPM1, NPM3, NCL, UBF-immunoreactive nucleoli are observed in CA1 at stages III-IV and more markedly at V-VI, with a similar but less severe pattern in DG.
“reduced numbers of nucleoli, as revealed with Nissl stain, and reduced numbers of NPM1, NPM3, NCL and UBF‐immunoreactive nucleoli was observed in CA1 at stages III–IV, and more markedly at stages V–VI (Table 2). A similar pattern, although less severe, was seen in DG”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ ResultsNCL nucleolar immunostaining decreases in CA1 neurons with AD progression, and NCL localizes in cytoplasmic granules recognized as granulovacuolar degeneration in CA1 neurons at advanced AD stages.
“Decreased nucleolar immunostaining in CA1 neurons with disease progression was also observed for NCL. Curiously, NCL was localized in cytoplasmic granules recognized as granulovacuolar degeneration in CA1 neurons at advanced stages of AD”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ ResultsIn the CA1 region of AD cases at stages V-VI, NCL, NPM3, and UBTF mRNAs are reduced, while NPM1 mRNA levels are normal compared with MA.
“This was followed by significantly reduced expression of NCL, NPM3 and UBTF mRNAs, and normal NPM1 mRNA levels at stages V–VI (Table 1).”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown data§ ResultsReduced eEF2 protein levels are identified in CA1 only at AD stages I-II and normalize thereafter.
“Reduced eEF2 protein levels were identified only at stages I–II and normalized thereafter.”
Quote in the paperSubstantial claimMay combine two claims. The quote only partly states this claim.
Findingown data§ ResultsIn CA1, RPL5 mRNA is up-regulated and RPL23A and RPS5 down-regulated at AD stages III-IV compared with MA.
“RPL5 mRNA was up‐regulated and RPL23A and RPS5 down‐regulated at stages II–IV.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ ResultsIn CA1, RPL5 and RPL30 mRNAs are up-regulated at AD stages V-VI, but RPL21, RPL23A, RPL26, RPL31, RPS6, RPS10, RPS13, RPS16 and RPS17 are significantly down-regulated compared with MA.
“RPL5 and RPL30 mRNAs were up‐regulated at stages V–VI, but RPL21, RPL23A, RPL26, RPL31, RPS6, RPS10, RPS13, RPS16 and RPS17 significantly down‐regulated at stages V–VI (Table 3).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ DiscussionThe expression of NPM1 and UBTF mRNAs, 28sRNA, RPL5, RPL26, RPS5 and RPS6 mRNAs, and eEF2 protein is altered in the CA1 at stages I-II of Braak and Braak.
“the expression of NPM1 and UBTF mRNAs, 28sRNA, RPL5, RPL26, RPS5 and RPS6 mRNAs, and eEF2 protein is altered in the CA1 at stages I–II of Braak and Braak.”
Quote in the paperSubstantial claimMay combine two claims.
Premisecitation§ DiscussionAltered expression of nucleolar chaperones and factors involved in rRNA synthesis results in nucleolar stress which in turn leads to impaired ribosomal biogenesis.
“It is known that altered expression of nucleolar chaperones and factors involved in rRNA synthesis results in nucleolar stress which in turn leads to impaired ribosomal biogenesis 4, 58, 69, 79.”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [4] 4. Avitabile D, Bailey B, Cottage CT, Sundararaman B, Joyo A, McGregor M et al (2011) Nucleolar stress is an early response to myocardial damage involving nucleolar proteins nucleostemin and nucleophosmin. Proc Natl Acad Sci USA 108:6145–6150. [DOI] [PMC free article] [PubMed] [Google Scholar]
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- cites [69] 69. McKeown PC, Shaw PJ (2009) Chromatin: linking structure and function in the nucleolus. Chromosoma 118:11–23. [DOI] [PubMed] [Google Scholar]
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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ DiscussionUBF encoded by UBTF is associated with NOR and is required for rDNA transcription by RNA polymerase 1.
“UBF encoded by UBTF (upstream binding transcription factor, RNA polymerase I gene) is associated with NOR and is required for rDNA transcription by RNA polymerase 1 83.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [83] 83. Roussel P, André C, Masson C, Géraud G, Hernandez‐Verdun D (1993) Localization of the RNA polymerase I transcription factor hUBF during the cell cycle. J Cell Sci 104:327–337. [DOI] [PubMed] [Google Scholar]
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May combine two claims.
Interpretationown data§ DiscussionImmunohistochemistry shows reduced immunoreactivity in remaining nucleoli at middle and advanced stages of the disease, suggesting declining immunoreactivity in surviving cells.
“In addition, immunohistochemistry shows reduced immunoreactivity in remaining nucleoli at middle and advanced stages of the disease thus suggesting declining immunoreactivity in surviving cells.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
Premisecitation§ DiscussionNCL, NPM1/B23 and NPM3 are major nucleolar proteins acting as histone-binding chaperones required for chromatin compacting and regulation of rRNA transcription.
“NCL, NPM1/B23 and NPM3 are major nucleolar proteins acting as histone‐binding chaperones required for chromatin compacting and regulation of rRNA transcription 2, 18, 33, 37, 40, 41, 53, 65, 72, 74, 77, 97, 102, 104.”
Quote in the paperSubstantial claim0 of 10 sources checked- cites [2] 2. Angelov D, Bondarenko VA, Almagro S, Menoni H, Mongelard F, Hans F et al (2006) Nucleolin is a histone chaperone with FACT like activity and assists remodeling of nucleosomes. EMBO J 25:1669–1679. [DOI] [PMC free article] [PubMed] [Google Scholar]
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Classified as probably not a substantial claim. May combine two claims.
Study design and conductnone given§ IntroductionDensitometric protein values were normalized with β-actin levels and expressed as an optical density ratio.
“Densitometric protein values were normalized with β‐actin levels and expressed as an optical density ratio.”
Quote in the paperSubstantial claimMay combine two claims.
Premisecitation§ IntroductionThe nuclear organizer region (NOR) surface/total nucleus surface is reduced and the rDNA promoter is hyper-methylated in AD, suggesting epigenetic silencing of rDNA at very precise times of AD progression.
“Moreover, the nuclear organizer region (NOR) surface/total nucleus surface is reduced 22, 28, and the rDNA promoter is hyper‐methylated in AD, thus suggesting epigenetic silencing of rDNA at very precise times of AD progression 80.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [22] 22. da Silva AM, Payão SL, Borsatto B, Bertolucci PH, Smith MA (2000) Quantitative evaluation of rRNA in Alzheimer's disease. Mech Ageing Dev 120:57–64. [DOI] [PubMed] [Google Scholar]
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Study design and conductnone given§ IntroductionBrain samples were obtained following European Union legislation and approval of the local ethics committee.
“Brain samples were obtained from the Institute of Neuropathology HUB‐ICO‐IDIBELL Biobank following European Union legislation and the approval of the local ethics committee.”
Quote in the paperNot a substantial claimMay combine two claims.
Study design and conductnone given§ IntroductionMA cases had not suffered from neurologic or psychiatric diseases and did not have lesions in the neuropathological study.
“MA cases (n = 18) had not suffered from neurologic or psychiatric diseases, and did not have lesions in the neuropathological study (including vascular, hypoxic, and inflammatory).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown data§ IntroductionTo test specificity of immunoreaction, some sections were incubated without primary antibodies; the staining was negative.
“To test the specificity of immunoreaction some sections were incubated without the primary antibodies; the staining was negative.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone given§ IntroductionParallel assays for each sample were performed using TaqMan probes for β-glucuronidase (GUS-β) and X-prolyl aminopepidase P1 (XPNPEP1) as endogenous controls.
“Parallel assays for each sample were performed using TaqMan probes for β‐glucuronidase (GUS‐β) and X‐prolyl aminopepidase P1 (XPNPEP1) as endogenous controls.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown data§ IntroductionRNA integrity number (RIN) values of the samples varied from 6.3 to 7.9.
“The RIN values of the samples varied from 6.3 to 7.9.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown data§ AbstractThese findings show alterations in the protein synthesis machinery in AD involving the nucleolus, nucleus and ribosomes in the hippocampus in AD some of them starting at first stages (I-II) preceding neuron loss.
“These findings show alterations in the protein synthesis machinery in AD involving the nucleolus, nucleus and ribosomes in the hippocampus in AD some of them starting at first stages (I–II) preceding neuron loss.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductnone given§ IntroductionCases with additional pathologies including Lewy body diseases, tauopathies, vascular diseases, TDP-43pathies, and metabolic syndrome were excluded.
“Cases with additional pathologies, including Lewy body diseases, tauopathies (particularly argyrophilic grain disease), vascular diseases, TDP‐43pathies, and metabolic syndrome were excluded.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DiscussionTau binds to double- and single-stranded DNA in vitro.
“Tau binds to double‐ and single‐strands of DNA in vitro 51, 61, 78”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [51] 51. Hua Q, He RQ, Haque N, Qu MH, del Carmen Alonso A, Grundke‐Iqbal I, Iqbal K (2003) Microtubule associated protein tau binds to double‐stranded but not single‐stranded DNA. Cell Mol Life Sci 60:413–421. [DOI] [PMC free article] [PubMed] [Google Scholar]
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Premisecitation§ DiscussionHistone deacetylase 6 interacts with the microtubule-associated protein tau.
“Histone deacetylase 6 interacts with the microtubule‐associated protein tau 25.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [25] 25. Ding H, Dolan PJ, Johnson GV (2008) Histone deacetylase 6 interacts with the microtubule‐associated protein tau. J Neurochem 106:2119–2130. [DOI] [PMC free article] [PubMed] [Google Scholar] source
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Premisecitation§ IntroductionSeminal studies identified altered composition of ribosomes, abnormal expression levels of certain transcription factors, and impaired protein synthesis in cortical areas in cases with mild cognitive impairment and dementia caused by AD.
“Seminal studies identified altered composition of ribosomes and abnormal expression levels of certain transcription factors, and impaired protein synthesis in cortical areas in cases with mild cognitive impairment and dementia caused by AD 26, 34, 62, 64, 84.”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [26] 26. Ding Q, Markesbery WR, Chen Q, Li F, N. Keller JN (2005) Ribosome dysfunction is an early event in Alzheimer's disease. J Neurosci 25:9171–9175. [DOI] [PMC free article] [PubMed] [Google Scholar]
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Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ DiscussionBoth the proline-rich domain and the microtubule-binding domain of tau contribute to its interaction with DNA.
“both the proline‐rich domain and the microtubule‐binding domain of tau are known to contribute to its interaction with DNA 107.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [107] 107. West MJ, Kawas CH, Stewart WF, Rudow GL, Troncoso JC (2004) Hippocampal neurons in pre‐clinical Alzheimer's disease. Neurobiol Aging 25:1205–1212. [DOI] [PubMed] [Google Scholar] source
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Study design and conductnone given§ IntroductionTaqMan PCR assays for each gene were performed in duplicate.
“TaqMan PCR assays for each gene were performedin duplicate.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DiscussionNuclear tau protects DNA from denaturation in vitro.
“protects DNA from denaturation in vitro 51, 52”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [51] 51. Hua Q, He RQ, Haque N, Qu MH, del Carmen Alonso A, Grundke‐Iqbal I, Iqbal K (2003) Microtubule associated protein tau binds to double‐stranded but not single‐stranded DNA. Cell Mol Life Sci 60:413–421. [DOI] [PMC free article] [PubMed] [Google Scholar]
Not checked in the free run.
- cites [52] 52. Hua Q, He R (2005) Tau could protect DNA double helix structure. Biochem Biophys Acta 1645:205–211. [DOI] [PubMed] [Google Scholar]
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May combine two claims.
Premisecitation§ IntroductionThe main modifications in AD cortex include reduced rRNA levels, increased RNA oxidation, and reduced capacity of isolated polyribosomes to incorporate S35 methionine into protein.
“The main modifications were reduced rRNA levels, increased RNA oxidation as shown by increased 8‐hydroxyguanosine immunoreactivity, and reduced capacity of isolated polyribosomes to incorporate S35 methionine into protein 26, 27, 48, 75, 76, 90, 91.”
Quote in the paperSubstantial claim0 of 7 sources checked- cites [26] 26. Ding Q, Markesbery WR, Chen Q, Li F, N. Keller JN (2005) Ribosome dysfunction is an early event in Alzheimer's disease. J Neurosci 25:9171–9175. [DOI] [PMC free article] [PubMed] [Google Scholar]
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- cites [27] 27. Ding Q, Markesbery WR, Cecarini V, Keller JN (2006) Decreased RNA, and increased RNA oxidation, in ribosomes from early Alzheimer's disease. Neurochem Res 31:705–710. [DOI] [PubMed] [Google Scholar]
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Premisecitation§ DiscussionProtein tau is localized in the nucleus of neuroblastoma cells, non-neural cells, and neurons in human brain.
“Protein tau is localized in the nucleus of neuroblastoma cells 44, 45, 66, 100, 105, non‐neural cells 21, 68, 101, and neurons in human brain 14.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [44] 44. Greenwood JA, Johnson GWW (1995) Localization and in situ phosphorylation state of nuclear tau. Exp Cell Res 220:332–337. [DOI] [PubMed] [Google Scholar]
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Premisecitation§ DiscussionNuclear tau confers stability to DNA.
“confers stability to DNA 15, 92.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [15] 15. Brady RM, Zinkowski RP, Binder LI. Camero S, Benítez MJ, Barrantes A et al (2014) Tau protein provides DNA with thermodynamic and structural features which are similar to those found in histone‐DNA complex. J Alzheimers Dis 39:649–660. [DOI] [PubMed] [Google Scholar]
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Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DiscussionSeveral studies have shown altered gene expression in the post-mortem brain of cases with Alzheimer's disease and related animal models.
“Several studies have shown altered gene expression in the post‐mortem brain of cases with AD and related animal models 7, 67, 99.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [7] 7. Bossers K, Wirz KT, Meerhoff GF, Essing AH, van Dongen JW, Houba P et al (2010) Concerted changes in transcripts in the prefrontal cortex precede neuropathology in Alzheimer's disease. Brain 133:3699–3723. [DOI] [PubMed] [Google Scholar] source
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May combine two claims.
Interpretationown data§ DiscussionThis is the first study showing altered pathways related to protein synthesis, including altered mRNA and protein expression of certain nucleolar chaperones, factors linked to DNA polymerases, altered methylation and acetylation of specific histones, altered expression of nuclear tau, abnormal rRNA expression, altered expression of several RPL and RPS genes, and altered expression of certain initi
“this is the first study showing altered pathways related to protein synthesis including altered mRNA and protein expression of certain nucleolar chaperones, factors linked to DNA polymerases, altered methylation and acetylation of specific histones, altered expression of nuclear tau, abnormal rRNA expression, altered expression of several RPL and RPS genes, and altered expression of certain initi”
Quote in the paperSubstantial claim- Rests on an assumption: Altered expression of components of the protein synthesis machinery reflects altered protein synthesis in Alzheimer's disease.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DiscussionProgressive atrophy of the hippocampus, as visualized with several neuroimaging techniques and in a particular clinical context, is currently used as a biomarker of Alzheimer's disease progression.
“Progressive atrophy of the hippocampus, as visualized with several neuroimaging techniques and in a particular clinical context, is currently used as a biomarker of AD progression 8.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [8] 8. Boutet C, Chupin M, Lehéricy S, Marrakchi‐Kacem L, Epelbaum S, Poupon C et al (2014) Detection of volume loss in hippocampal layers in Alzheimer's disease using 7 T MRI: a feasibility study. Neuroimage Clin 5:341–348. [DOI] [PMC free article] [PubMed] [Google Scholar]
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Premisecitation§ DiscussionMorphological and immunohistochemical studies have shown reduced dendritic arbors, reduced numbers of synapses, and reduced synaptic protein markers both in the CA1 region of the hippocampus and in the DG.
“morphological and immunohistochemical studies have shown reduced dendritic arbors, reduced numbers of synapses, and reduced synaptic protein markers both in the CA1 region of the hippocampus and in the DG 32, 36, 56, 82, 86, 87, 88, 89.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [32] 32. Einstein G, Buranosky R, Crain BJ (1994) Dendritic pathology of granule cells in Alzheimer's disease is unrelated to neuritic plaques. J Neurosci 14:5077–5088. [DOI] [PMC free article] [PubMed] [Google Scholar]
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Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DiscussionThis change has been mainly interpreted as being the result of loss of afferents to the DG and to the loss of neurons in the CA1 region of the hippocampus.
“This change has been mainly interpreted as being the result of loss of afferents to the DG and to the loss of neurons in the CA1 region of the hippocampus 107.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [107] 107. West MJ, Kawas CH, Stewart WF, Rudow GL, Troncoso JC (2004) Hippocampal neurons in pre‐clinical Alzheimer's disease. Neurobiol Aging 25:1205–1212. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
The paper relies on this without support.
Reduced protein synthesis is one of the most plausible causes of neuron atrophy in AD.
“However, the cause of neuron atrophy has not been examined in detail although one of the most plausible causes is reduced protein synthesis.”
The authors state this as an assumption.
Modifications in the hippocampus with disease progression have not been assessed.
“Modifications in the hippocampus with disease progression have not been assessed.”
The paper relies on this without support.
Lack of perfect match between mRNA levels and corresponding proteins can be explained by the concomitant activity of epigenetic factors as several types of non-coding RNAs.
“Lack of perfect match between mRNA levels and corresponding proteins, as seen in relation with increased NPM1 and NPM3 mRNAs and decreased NPM1 and NPM3 protein levels in the CA1 region of the hippocampus at stages III–IV, is not rare in human neurodegenerative diseases and can be explained by the concomitant activity of epigenetic factors as several types of non‐coding RNAs.”
The paper relies on this without support.
Altered expression of components of the protein synthesis machinery reflects altered protein synthesis in Alzheimer's disease.
“Together these observations support altered protein synthesis with disease progression.”
“It can be argued that none of these alterations proves that protein synthesis is impaired in AD.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
A recent study on post-mortem AD brains revealed translocation of intranuclear tau to the soma in diseased brains compared to controls, indicating that intranuclear tau may also play a role in its pathogenesis.
“A recent study on post-mortem AD brains revealed translocation of intranuclear tau to the soma in diseased brains compared to controls [57], indicating that intranuclear tau may also play a role in its pathogenesis.”
From DNA repair deficiency and senescence in concussed professional athletes involved in contact sports (2019) · cites this paper as [57]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Abstract and results name different acetylated histones
MajorThe abstract identifies the decreased acetylation marker as H3K12ac, whereas the results identify it as H4K12ac. These refer to different histones, so the paper is inconsistent about which marker decreased.
“Histone modifications dimethylated histone H3K9 (H3K9me2) and acetylated histone H3K12 (H3K12ac) are decreased in CA1.”
“H3K9me2 (Figure 3A–D) and H4K12ac (Figure 3E–H) staining declined in CA1 and DG neurons with disease progression (Table 2).”
Western-blot antibody reference points to an mRNA table
MinorThe western-blot methods cite Table 3 for primary antibodies, but Table 3 is labeled as mRNA expression of ribosomal proteins, not antibody information.
“then incubated overnight at 4°C with the appropriate primary antibody (Table 3).”
“Table 3. mRNA expression of ribosomal proteins in the DG and CA1 region of the hippocampus of MA and AD cases.”
Early CA1 result names RPS26 instead of RPS6
MinorThe results name RPS26 as down-regulated at stages I-II, but the final comments name RPS6 for the same early CA1 finding. Table 3 lists RPS6, not RPS26.
“Regarding CA1, RPL5 and RPL26 mRNAs were up‐regulated and RPS5 and RPS26 mRNAs down‐regulated in AD I‐II in relation to MA cases.”
“It is worth stressing that the expression of NPM1 and UBTF mRNAs, 28sRNA, RPL5, RPL26, RPS5 and RPS6 mRNAs, and eEF2 protein is altered in the CA1 at stages I–II of Braak and Braak.”
The citation lists haven’t been fetched yet
References 108 · Cited by 245
Research works printed but not linked: 1
- Stelzl U, 2001, Ribosomal proteins: role in ribosomal function, Encyclopedia Life Sci, 1
- Authors
- Hernández‐Ortega, K., Garcia‐Esparcia, P., Gil, L., Lucas, J. J., & Ferrer, I.
- Affiliations
- Bellvitge University Hospital (ES)
- Universidad Alfonso X el Sabio (ES)
- Consejo Superior de Investigaciones Científicas (ES)
- Institute of Neuropathology, Service of Pathologic Anatomy, IDIBELL‐Bellvitge University Hospital, University of Barcelona, Hospitalet de Llobregat Spain
- Venue
- Brain Pathology
- Publisher
- Wiley
- Published
- 2015-12-14
- Volume
- 26
- Issue
- 5
- Pages
- 593-605
- ISSN
- 1015-6305 (ISSN-L)
- 1750-3639
- PMC
- PMC8029302
- OpenAlex
- W1858579514
- Semantic Scholar
- b88a0dead357172dc77c08c2d7dc3c16400e9841
- Cited by
- 245
- References
- 108
- Citations by year
- 2026: 35 · 2025: 20 · 2024: 26 · 2023: 29 · 2022: 24 · 2021: 29 · 2020: 25 · 2019: 27 · 2018: 8 · 2017: 16 · 2016: 5 · 2015: 1
- FWCI
- 7.37
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, public-domain)
- Funders
- Seventh Framework Programme of the European Commission (278486)
- DEVELAGE and the Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III - Fondos FEDER, a way to build Europe FIS (PIE14/00034, PI14/00757)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, protein synthesis, ribosome, nucleolus, hippocampus, CA1, dentate gyrus, nucleolin, nucleophosmin, UBTF, histone modifications, H3K9me2, neurofibrillary tangles, 28S rRNA, ribosomal proteins, translation initiation factors, eIF2α, eIF3, eIF5, elongation factor 2, hippocampal atrophy, synaptic loss
- MeSH terms
- Adult, Aged, Alzheimer Disease, Cell Count, Cell Nucleus, Female, Gene Expression Regulation, Hippocampus, Humans, Male, Middle Aged, Neurons, Nuclear Proteins, Ribosomal Proteins, Ribosomes, Case-Control Studies, tau Proteins, Disease Progression, Pol1 Transcription Initiation Complex Proteins, Transcriptional Elongation Factors
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