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Cited by 47Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchEndoplasmic Reticulum Stress and Disease

PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease

Open access
Morel, Milena, Couturier, Julien, Lafay‐Chebassier, Claire, Paccalin, Marc, Page, Guylène·2009·Journal of Cellular and Molecular Medicine
DOI 10.1111/j.1582-4934.2009.00849.xPMC PMC3828860
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Abstract

Introduction Control of translation Dysfunctions of protein synthesis mediated by PKR‐ and mTOR‐dependent signalling pathways Crosslink between the up‐regulation of PKR/eIF2α and the down‐regulation of mTOR/RS6K in AD PKR: a potential biomarker of AD diagnosis Conclusion and perspectives Amyloid β‐peptide (Aβ) deposits and neurofibrillary tangles are key hallmarks in Alzheimer's disease (AD). Aβ stimulates many signal transducers involved in the neuronal death. However, many mechanisms remain to be elucidated because no definitive therapy of AD exists. Some studies have focused on the control of translation which involves eIF2 and eIF4E, main eukaryotic factors of initiation. The availability of these factors depends on the activation of the double‐stranded RNA‐dependent protein kinase (PKR) and the mammalian target of rapamycin (mTOR), respectively. mTOR positively regulates the translation while PKR results in a protein synthesis shutdown. Many studies demonstrated that the PKR signalling pathway is up‐regulated in cellular and animal models of AD and in the brain of AD patients. Interestingly, our results showed that phosphorylated PKR and eIF2α levels were significantly increased in lymphocytes of AD patients. These modifications were significantly correlated with cognitive and memory test scores performed in AD patients. On the contrary, the mTOR signalling pathway is down‐regulated in cellular and animal models of AD. Recently, we showed that p53, regulated protein in development and DNA damage response 1 and tuberous sclerosis complex 2 could represent molecular links between PKR and mTOR signalling pathways. PKR could be an early biomarker of the neuronal death and a critical target for a therapeutic programme in AD.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that the double-stranded RNA-dependent protein kinase (PKR)/eIF2α pathway is up-regulated in Alzheimer's disease (AD) brains, cellular and animal models, and patient lymphocytes, while the mTOR/p70S6K pathway is down-regulated. The authors propose PKR as an early biomarker of neuronal death and a critical therapeutic target, with p53, Redd1 and TSC2 as molecular links between the two pathways.

Key findings

  • Phosphorylated PKR and eIF2α levels were significantly increased in lymphocytes of AD patients and negatively correlated with cognitive and memory test scores (higher PKR, lower score).
  • In an initial lymphocyte cohort, the PT389-p70S6K/total p70S6K ratio was reduced in AD patients (n=26) versus controls (n=28) and positively correlated with MMSE scores; however, in a larger cohort no significant differences were found for PT1462-TSC2 (control 2.39 ± 0.59, n=36; AD 2.48 ± 0.51, n=50), PS2448-mTOR (control 0.9 ± 0.1, n=38; AD 1.34 ± 0.2, n=49) or PT389-p70S6K (control 4.83 ± 1.01, n=32; AD 3.87 ± 0.53, n=50).
  • In AD lymphocytes, p53 and Redd1 gene expression, p53 activation and Redd1 protein levels were significantly higher than in age-matched controls, but were not correlated with MMSE scores; PKR siRNA transfection in Aβ42-treated SH-SY5Y cells decreased the p66 isoform of p53 and Redd1 transcription and increased phosphorylated TSC2.
  • In APPSL/PS1 KI mice, Pt451-PKR and PS51-eIF2α were increased, with PKR up-regulated as early as 3 months of age before massive neuronal loss at 6 months; the number of mononuclear cells was 43% higher in AD patients than controls.

Methods

  • Narrative review of the literature on translational control (eIF2/eIF4E, PKR, mTOR) in AD, integrating the authors' own published and unpublished data.
  • Evidence drawn from AD patient lymphocytes and blood cells, post-mortem AD brain tissue, neuroblastoma (SH-SY5Y) cell cultures exposed to Aβ, and APP/PS1 transgenic mouse models (APPsl, APPsl/PS1, APPSL/PS1 KI).
  • Main analyses cited include Western blot quantification of phosphorylated proteins, statistical correlations with MMSE and memory scores, and PKR gene silencing (siRNA) experiments.

Limitations

  • Stated by the paper: PKR is not specific to AD, being active in Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis, and in infectious, inflammatory and ischemic pathology without cognitive decline; the authors therefore suggest PKR may be an early biomarker of cell death rather than of cognitive decline.
  • Stated by the paper: PKR is a constitutive protein and all its physiological roles are unknown, so the appropriate inhibitor concentration or neuron-directed strategy remains to be determined.
  • Evident from the text: the Braak score was not indicated in the cited patient studies localizing Pt451-PKR; the authors note a paradox whereby PKR up-regulation in mononuclear cells does not lead to the cell death seen in neurons, and they offer only hypotheses for this discrepancy; several key supporting results are described as unpublished or submitted data.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1111/j.1582-4934.2009.00849.x

Cites

179 of 179 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

39 of 130 cited sources checked · 20 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    In cells deficient for PKR or containing a dominant-negative form, there is substantial resistance to apoptosis.

    “Conversely, in cells deficient for the kinase or containing a dominant-negative form, there is substantial resistance to apoptosis [30, 61, 63].”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [30] Chang RC Suen KC Ma CH Involvement of double-stranded RNA-dependent protein kinase and phosphorylation of eukaryotic initiation factor-2alpha in neuronal degeneration J Neurochem 2002 83 1215 25 12437593 source

      The section on vulnerability to Aβ peptide toxicity reports significantly fewer apoptotic cells among neurons expressing dominant-negative PKR. The PKR-knockout results (p. 1221) likewise show a much smaller increase in apoptosis after Aβ exposure, but the Discussion says those neurons did not entirely escape toxicity. The evidence concerns Aβ-induced neuronal apoptosis, not resistance to apoptosis generally. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [61] Balachandran S Barber GN PKR in innate immunity, cancer, and viral oncolysis Methods Mol Biol 2007 383 277 301 18217692 source
    • cites [63] Srivastava SP Kumar KU Kaufman RJ Phosphorylation of eukaryotic translation initiation factor 2 mediates apoptosis in response to activation of the double-stranded RNA-dependent protein kinase J Biol Chem 1998 273 2416 23 9442091 source
  • Premisecitation

    Phosphorylation of PKR and eIF2α is associated with degenerating neurons in AD brains.

    “previous reports revealed that phosphorylation of PKR and eIF2α was associated with degenerating neurons in AD brains [50, 95, 96].”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [50] Chang RC Wong AK Ng HK Phosphorylation of eukaryotic initiation factor-2alpha (eIF2alpha) is associated with neuronal degeneration in Alzheimer's disease Neuroreport 2002 13 2429 32 12499843 source
    • cites [95] Onuki R Bando Y Suyama E An RNA-dependent protein kinase is involved in tunicamycin-induced apoptosis and Alzheimer's disease EMBO J 2004 23 959 68 14765129 PMC380987 source

      The section “Levels of nuclear PKR in AD brain tissue” reports elevated phosphorylated PKR in AD brain tissue and suggests an association with AD pathology in neurons. The paper mentions eIF2α phosphorylation as a pathway involving PKR, but does not report phosphorylated eIF2α in AD brains. Its Discussion also notes that neurons with aggregated PKR had not apparently undergone apoptosis, so the evidence does not directly establish an association with degenerating neurons. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [96] Peel AL PKR activation in neurodegenerative disease J Neuropathol Exp Neurol 2004 63 97 105 14989595 source
  • Premisecitation

    PKR can induce dephosphorylation of 4E-BPs by increasing the activity of phosphatase 2A after its interaction with the regulatory subunit B56α, leading to cell apoptosis.

    “PKR can induce dephosphorylation of the proteins 4E-BPs by increasing the activity of the phosphatase 2A after its interaction with the regulatory subunit B56α, leading to cell apoptosis [82–84].”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [82] Ruvolo VR Kurinna SM Karanjeet KB PKR regulates B56(alpha)-mediated BCL2 phosphatase activity in acute lymphoblastic leukemia-derived REH cells J Biol Chem 2008 283 35474 85 18957415 PMC2602900 source

      The Abstract and the section on PKR suppression in REH cells link PKR, B56α-regulated mitochondrial PP2A activity, and apoptosis. They identify BCL2—not 4E-BPs—as the protein dephosphorylated in this pathway. A search for 4E-BPs and 4E-BP1 found no passage supporting that part of the claim. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [83] Jeffrey IW Bushell M Tilleray VJ Inhibition of protein synthesis in apoptosis: differential requirements by the tumor necrosis factor alpha family and a DNA-damaging agent for caspases and the double-stranded RNA-dependent protein kinase Cancer Res 2002 62 2272 80 11956083
    • cites [84] Xu Z Williams BR The B56alpha regulatory subunit of protein phosphatase 2A is a target for regulation by double-stranded RNA-dependent protein kinase PKR Mol Cell Biol 2000 20 5285 99 10866685 PMC85978 source

      The Results and Discussion (page unavailable) support a proposed mechanism in which PKR phosphorylates B56α, increases PP2A activity, and decreases phosphorylation of eIF4E—not 4E-BPs. The Discussion mentions apoptosis only as a possible effect of altered PP2A activity; it does not establish that this pathway leads to apoptosis. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
  • Premisecitation

    Aβ neurotoxicity is associated with an increased PKR and eIF2α phosphorylation linked to increased intracellular calcium and caspase-8 activation following Aβ exposure in vitro.

    “Another report demonstrated in vitro that Aβ neurotoxicity was associated with an increased PKR and eIF2α phosphorylation linked to increased intracellular calcium and caspase-8 activation following Aβ exposure [28, 30].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [28] Suen KC Yu MS So KF Upstream signaling pathways leading to the activation of double-stranded RNA-dependent serine/threonine protein kinase in beta-amyloid peptide neurotoxicity J Biol Chem 2003 278 49819 27 12975376 source
    • cites [30] Chang RC Suen KC Ma CH Involvement of double-stranded RNA-dependent protein kinase and phosphorylation of eukaryotic initiation factor-2alpha in neuronal degeneration J Neurochem 2002 83 1215 25 12437593 source

      The Discussion reports increased PKR and eIF2α phosphorylation during Aβ-induced neuronal apoptosis and links pathway activation to increased intracellular calcium. The time-course section reports caspase-3 activity after Aβ exposure, not caspase-8 activation; that part of the claim is unsupported by this source. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
  • Premisecitation

    p53 activation is able to inhibit the activity of mTOR through a pathway involving the subsequent activation of TSC1 and TSC2.

    “Furthermore, reports showed that p53 activation is able to inhibit the activity of mTOR through a pathway involving the subsequent activation of TSC gene products TSC1 and TSC2, which are tumour suppressors and negative regulators of mTOR [78, 103–105].”
    Quote in the paperSubstantial claim1 of 4 sources checked
    • cites [78] Krymskaya VP Tumour suppressors hamartin and tuberin: intracellular signalling Cell Signal 2003 15 729 39 12781866 source
    • cites [103] Feng Z Hu W de Stanchina E The regulation of AMPK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways Cancer Res 2007 67 3043 53 17409411 source
    • cites [104] Levine AJ Feng Z Mak TW Coordination and communication between the p53 and IGF-1-AKT-TOR signal transduction pathways Genes Dev 2006 20 267 75 16452501 source
    • cites [105] Feng Z Zhang H Levine AJ The coordinate regulation of the p53 and mTOR pathways in cells Proc Natl Acad Sci USA 2005 102 8204 9 15928081 PMC1142118 source
  • May combine two claims. 27
  • Classified as probably not a substantial claim. 19

  • May combine two claims.

    Premisecitation

    Activation of PKR can either induce apoptotic cell death or at least enhance this process when apoptosis is initiated by other agents.

    “Several studies established that activation of PKR can either induce apoptotic cell death or at least enhance this process when apoptosis is initiated by other agents [61, 62].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [61] Balachandran S Barber GN PKR in innate immunity, cancer, and viral oncolysis Methods Mol Biol 2007 383 277 301 18217692 source
    • cites [62] Der SD Yang YL Weissmann C A double-stranded RNA-activated protein kinase-dependent pathway mediating stress-induced apoptosis Proc Natl Acad Sci USA 1997 94 3279 83 9096384 PMC20360 source

  • May combine two claims.

    Findingcitation

    PKR and eIF2α levels were negatively correlated with cognitive and memory test scores in AD patients, with higher PKR expression associated with lower cognitive test scores.

    “These modifications were significantly correlated with cognitive and memory test scores performed in AD patients.”
    • Also stated in: § Dysfunctions of protein synthesis mediated by PKR- and mTOR-dependent signalling pathways · plain
      “These PKR and eIF2α levels were negatively correlated with cognitive and memory test scores performed in AD patients: the higher expression of PKR with the lower cognitive test score [101, 102].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [101] Paccalin M Pain-Barc S Pluchon C Activated mTOR and PKR kinases in lymphocytes correlate with memory and cognitive decline in Alzheimer's disease Dement Geriatr Cogn Disord 2006 22 320 6 16954686 source
    • cites [102] Damjanac M Page G Ragot S PKR, a cognitive decline biomarker, can regulate translation via two consecutive molecular targets p53 and Redd1 in lymphocytes of AD patients J Cell Mol Med 2009 [Epub ahead of press] PMC6529964 19210572 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    mTOR can phosphorylate eIF4G and ribosomal S6 kinases such as p70S6K, which phosphorylate eIF4B, enhancing its interaction with eIF3 and stimulating protein synthesis.

    “mTOR can also phosphorylate eIF4G, the ribosomal S6 kinases (RS6K) such as p70S6K which phosphorylate eIF4B, enhancing its interaction with eIF3 and stimulate protein synthesis [75–77] (Fig. 1).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [75] Ma XM Blenis J Molecular mechanisms of mTOR-mediated translational control Nat Rev Mol Cell Biol 2009 10 307 18 19339977 source
    • cites [76] Holz MK Ballif BA Gygi SP mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events Cell 2005 123 569 80 16286006 source

      The Discussion reports that mTOR/raptor phosphorylates S6K1, after which activated S6K1 phosphorylates eIF4B and phosphorylated eIF4B is recruited to the eIF3 preinitiation complex. The Results link this sequence to translation initiation. The paper describes mTOR phosphorylating 4E-BP1, followed by recruitment of eIF4G; it does not support the claim that mTOR phosphorylates eIF4G. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [77] Dufner A Thomas G Ribosomal S6 kinase signaling and the control of translation Exp Cell Res 1999 253 100 9 10579915 source

  • May combine two claims.

    Interpretationreasoning

    There are two different neuronal responses: some neurons are characterized by a highly reactive Akt/mTOR/RS6K signalling pathway involved in τ-hyperphosphorylation and in future NFTs, and other neurons display a total inhibition of PT389-p70/85S6K leading to the apoptotic process in AD.

    “Taken together, one may propose that there are two different neuronal responses: some neurons are characterized by a highly reactive Akt/mTOR/RS6K signalling pathway involved in τ-hyperphospho-rylation and in future NFTs and other neurons displayed a total inhibition of PT389-p70/85S6K leading to the apoptotic process in AD [91, 94].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [91] Damjanac M Rioux Bilan A Paccalin M Dissociation of Akt/PKB and ribosomal S6 kinase signaling markers in a transgenic mouse model of Alzheimer's disease Neurobiol Dis 2008 29 354 67 18023354 source
    • cites [94] Pei JJ Hugon J mTOR-dependent signalling in Alzheimer's disease J Cell Mol Med 2008 12 2525 32 19210753 PMC3828871 source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Redd1 is a new stress-induced protein and a negative regulator of mTOR through the TSC1/TSC2 complex.

    “Redd1 is a new stress-induced protein and is known as a negative regulator of mTOR through TSC1/TSC2 complex [106–115].”
    Quote in the paperNot a substantial claim6 of 10 sources checked
    • cites [106] Ellisen LW Ramsayer KD Johannessen CM REDD1, a developmentally regulated transcriptional target of p63 and p53, links p63 to regulation of reactive oxygen species Mol Cell 2002 10 995 1005 12453409 source

      The Results report that REDD1 protein increases after ionizing radiation or MMS treatment and identify REDD1 as the stress-induced gene RTP801 (page not provided). The cited paper does not establish that REDD1 negatively regulates mTOR through the TSC1/TSC2 complex; its Discussion instead focuses on regulation of reactive oxygen species. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [107] Jin HO An S Lee HC Hypoxic condition- and high cell density-induced expression of Redd1 is regulated by activation of hypoxia-inducible factor-1alpha and Sp1 through the phosphatidylinositol 3-kinase/Akt signaling pathway Cell Signal 2007 19 1393 403 17307335 source
    • cites [108] Brugarolas J Lei K Hurley RL Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex Genes Dev 2004 18 2893 904 15545625 PMC534650 source

      The Discussion (page not supplied) describes Redd1 as stress-induced and reports that its suppression of mTOR signaling requires Tsc2. It presents signaling through the Tsc1/Tsc2 complex as the simplest model, however, and says a parallel pathway cannot be excluded; the claim states that mechanism more definitively than the paper does. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [109] Corradetti MN Inoki K Guan KL The stress-inducted proteins RTP801 and RTP801L are negative regulators of the mammalian target of rapamycin pathway J Biol Chem 2005 280 9769 72 15632201 source
    • cites [110] Shoshani T Faerman A Mett I Identification of a novel hypoxia-inducible factor 1-responsive gene, RTP801, involved in apoptosis Mol Cell Biol 2002 22 2283 93 11884613 PMC133671 source
    • cites [111] Sofer A Lei K Johannessen CM Regulation of mTOR and cell growth in response to energy stress by REDD1 Mol Cell Biol 2005 25 5834 45 15988001 PMC1168803 source
    • cites [112] Ellisen LW Growth control under stress: mTOR regulation through the REDD1-TSC pathway Cell Cycle 2005 4 1500 2 16258273 source
    • cites [113] Jozwiak J Jozwiak S Grzela T Positive and negative regulation of TSC2 activity and its effects on downstream effectors of the mTOR pathway Neuromolecular Med 2005 7 287 96 16391386 source
    • cites [114] Kimball SR Do AN Kutzler L Rapid turnover of the mTOR complex 1 (mTORC1) repressor REDD1 and activation of mTORC1 signaling following inhibition of protein synthesis J Biol Chem 2008 283 3465 75 18070882 PMC2654224 source
    • cites [115] Wang H Kubica N Ellisen LW Dexamethasone represses signaling through the mammalian target of rapamycin in muscle cells by enhancing expression of REDD1 J Biol Chem 2006 281 39128 34 17074751 source

  • May combine two claims.

    Premisecitation

    Endogenous Redd1 is required for both dissociation of endogenous TSC2/14-3-3 proteins and inhibition of mTOR in response to hypoxia.

    “A recent study showed that endogenous Redd1 is required for both dissociation of endogenous TSC2/14–3-3 proteins and inhibition of mTOR in response to hypoxia [127].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [127] DeYoung MP Horak P Sofer A Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14–3-3 shuttling Genes Dev 2008 22 239 51 18198340 PMC2192757 source

  • May combine two claims.

    Premisecitation

    PKR activates GSK-3β, which phosphorylates p53 in the nucleus and promotes the proteasomal degradation of p53 by Hdm2-dependent ubiquitination.

    “Interestingly, PKR activates GSK-3β, which phosphorylates p53 in nucleus and promotes the proteasomal degradation of p53 by the Hdm2-dependent ubiquitination [121].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [121] Baltzis D Pluquet O Papadakis AI The eIF2α kinases PERK and PKR activate glycogen synthase kinase 3 to promote the proteasomal degradation of p53 J Biol Chem 2007 282 31675 87 17785458 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    T cells can influence microglial differentiation.

    “In vitro data showed a ‘cross-talking’ between microglia and T cells, microglia can serve as antigen-presenting cells for Aβ-reactive T cells and, in turn, T cells themselves can influence microglial differentiation [161–163].”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [161] Monsonego A Imitola J Zota V Microglia-mediated nitric oxide cytotoxicity of T cells following amyloid betapep-tide presentation to Th1 cells J Immunol 2003 171 2216 24 12928365 source
    • cites [162] Monsonego A Zota V Karni A Increased T cell reactivity to amyloid beta protein in older humans and patients with Alzheimer disease J Clin Invest 2003 112 415 22 12897209 PMC166296 source

      In the passage labeled Figure 4 (page unavailable), the paper suggests that Aβ-reactive T cells might modulate microglial activation at plaque sites. It does not report that T cells influence microglial differentiation, or present in vitro data demonstrating that effect. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [163] Seguin R Biernacki K Prat A Differential effects of Th1 and Th2 lymphocyte supernatants on human microglia Glia 2003 42 36 45 12594735 source

  • May combine two claims.

    Interpretationcitation

    PKR also controls the state of phosphorylation of TSC2 perhaps through the activation of the proteasomal degradation of cyclin D1 involved in the increased phosphorylation of TSC2 when it is associated to CDK4/6.

    “Thus, PKR also controls this state of phosphorylation of TSC2 perhaps through the activation of the proteasomal degradation of cyclin D1 involved in the increased phosphorylation of TSC2 when it is associated to CDK4/6 [139].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [139] Zacharek SJ Xiong Y Shumway SD Negative regulation of TSC1-TSC2 by mammalian D-type cyclins Cancer Res 2005 65 11354 60 16357142 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Glial cells can mediate the permeability of the blood brain barrier to recruit specialized immune cells from the periphery such as T cells.

    “It is also known that glial cells can mediate the permeability of blood brain barrier to recruit specialized immune cells from the periphery such as T cells [164].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [164] Farfara D Lifshitz V Frenkel D Neuroprotective and neurotoxic properties of glial cells in the pathogenesis of Alzheimer's disease J Cell Mol Med 2008 12 762 80 18363841 PMC4401126 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    T-helper 1 cells can promote microglial cell activation through the secretion of IFN-γ.

    “T-helper 1 cells can promote microglial cell activation through the secretion of IFN-γ, which also up-regulates the expression major histocompatibility complex class II molecules by microglial cells, thereby enhancing the interaction between T cells and microglial cells [164, 165].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [164] Farfara D Lifshitz V Frenkel D Neuroprotective and neurotoxic properties of glial cells in the pathogenesis of Alzheimer's disease J Cell Mol Med 2008 12 762 80 18363841 PMC4401126 source
    • cites [165] Akiyama H Barger S Barnum S Inflammation and Alzheimer's disease Neurobiol Aging 2000 21 383 421 10858586 PMC3887148 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Microglia can serve as antigen-presenting cells for Aβ-reactive T cells.

    “In vitro data showed a ‘cross-talking’ between microglia and T cells, microglia can serve as antigen-presenting cells for Aβ-reactive T cells and, in turn, T cells themselves can influence microglial differentiation [161–163].”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [161] Monsonego A Imitola J Zota V Microglia-mediated nitric oxide cytotoxicity of T cells following amyloid betapep-tide presentation to Th1 cells J Immunol 2003 171 2216 24 12928365 source
    • cites [162] Monsonego A Zota V Karni A Increased T cell reactivity to amyloid beta protein in older humans and patients with Alzheimer disease J Clin Invest 2003 112 415 22 12897209 PMC166296 source

      The discussion following Figure 4 says Aβ is processed and presented by antigen-presenting cells to Aβ-reactive T cells. It also proposes that local APCs in the brain may capture Aβ, but it does not identify those cells as microglia or show microglia presenting Aβ to T cells. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [163] Seguin R Biernacki K Prat A Differential effects of Th1 and Th2 lymphocyte supernatants on human microglia Glia 2003 42 36 45 12594735 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    IFN-γ up-regulates the expression of major histocompatibility complex class II molecules by microglial cells.

    “T-helper 1 cells can promote microglial cell activation through the secretion of IFN-γ, which also up-regulates the expression major histocompatibility complex class II molecules by microglial cells, thereby enhancing the interaction between T cells and microglial cells [164, 165].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [164] Farfara D Lifshitz V Frenkel D Neuroprotective and neurotoxic properties of glial cells in the pathogenesis of Alzheimer's disease J Cell Mol Med 2008 12 762 80 18363841 PMC4401126 source
    • cites [165] Akiyama H Barger S Barnum S Inflammation and Alzheimer's disease Neurobiol Aging 2000 21 383 421 10858586 PMC3887148 source

  • May combine two claims.

    Findingcitation

    A progressive increase of apoptotic nuclei is observed at 3, 6 and 12 months of age in APPsl/PS1 KI mice and PKR is closely co-localized with DNA strand breaks in apoptotic nuclei of hippocampal neurons.

    “A progressive increase of apoptotic nuclei is also observed at 3, 6 and 12 months of age in these mice and PKR is closely co-localized with DNA strand breaks in apoptotic nuclei of hippocampal neurons [97].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [97] Page G Rioux Bilan A Ingrand S Activated double-stranded RNA-dependent protein kinase and neuronal death in models of Alzheimer's disease Neuroscience 2006 139 1343 54 16581193 source

  • May combine two claims.

    Findingown data

    In brains of PS1 KI and APPSL/PS1 KI mice, there was a significant decrease of p70/85S6K activation with very weak or no nucleocytoplasmic PT389-p70/85S6K staining in apoptotic neurons of APPSL/PS1 KI mice.

    “By contrast, a significant decrease of the p70/85S6K activation was observed in brains of PS1 KI and APPSL/PS1 KI mice with a very weak or no nucleocytoplasmic PT389-p70/85S6K staining in apoptotic neurons of APPSL/PS1 KI mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    In lymphocytes of AD patients, the PT389-p70S6K/total p70S6K ratio was reduced compared to control individuals and levels were positively correlated with MMSE scores.

    “Furthermore, in the lymphocytes of AD patients the PT389-p70S6K/total p70S6K ratio was reduced in AD patients (n= 26) compared to control individuals (n= 28) and levels were positively correlated with Mini Mental Status Examination (MMSE) scores [27].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Lafay-Chebassier C Paccalin M Page G mTOR/p70S6k signalling alteration by Abeta exposure as well as in APP-PS1 transgenic models and in patients with Alzheimer's disease J Neurochem 2005 94 215 25 15953364 source

  • May combine two claims.

    Findingown data

    In lymphocytes of AD patients, the expression of p53 and Redd1 genes, the activation of p53 and the levels of Redd1 protein were significantly higher compared to age-matched controls.

    “The results showed that the expression of p53 and Redd1 genes, the activation of p53 and the levels of Redd1 protein were significantly higher in lymphocytes of AD patients compared to age-matched controls.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Transfection of PKR siRNA to Aβ42-treated SH-SY5Y cells significantly decreased the p66 isoform of p53, the transcriptional expression of Redd1 and increased the levels of phosphorylated TSC2.

    “Recently, we showed that the transfection of PKR siRNA to Aβ42-treated SH-SY5Y cells significantly decreased the p66 isoform of p53, the transcriptional expression of Redd1 and increased the levels of phosphorylated TSC2 [129].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [129] Morel M Couturier J Pontcharraud R Evidence of molecular links between PKR and mTOR signalling pathways in Aβ neurotoxicity: role of p53, Redd1 and TSC2 Neurobiol Dis 2009 [Epub ahead of print 22 July 2009] 19631745 source

  • Probably not a substantial claim: may not pass S4 (based).

    Findingown data

    The authors demonstrated physical and functional interactions between PKR and FADD in Aβ neurotoxicity.

    “Recently, we demonstrated the physical and functional interactions between PKR and FADD in Aβ neurotoxicity (data submitted).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    PKR expression is increased with ageing or in neurodegenerative diseases such as AD, Parkinson's disease and Huntington's disease.

    “Several studies revealed an increased PKR expression with ageing [47] or in neurodegenerative diseases such as AD, Parkinson's disease, Huntington's disease [48–50]”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [47] Ladiges W Morton J Blakely C Tissue specific expression of PKR protein kinase in aging B6D2F1 mice Mech Ageing Dev 2000 114 123 32 10799709 source
    • cites [48] Peel AL Rao RV Cottrell BA Double-stranded RNA-dependent protein kinase, PKR, binds preferentially to Huntington's disease (HD) transcripts and is activated in HD tissue Hum Mol Genet 2001 10 1531 8 11468270 source
    • cites [49] Bando Y Onuki R Katayama T Double-strand RNA dependent protein kinase (PKR) is involved in the extrastriatal degeneration in Parkinson's disease and Huntington's disease Neurochem Int 2005 46 11 8 15567511 source
    • cites [50] Chang RC Wong AK Ng HK Phosphorylation of eukaryotic initiation factor-2alpha (eIF2alpha) is associated with neuronal degeneration in Alzheimer's disease Neuroreport 2002 13 2429 32 12499843 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    There are four different eIF2α kinases in mammals activated by different stress, which phosphorylate the same residue in eIF2α, resulting in down-regulation of general translation.

    “There are four different eIF2α kinases in mammals activated by different stress, PKR (double-stranded (ds) RNA-dependent protein kinase), PKR-like endoplasmic reticulum kinase, heme regulated kinase and amino-acid regulated kinase, which phosphorylate the same residue in eIF2α, resulting in down-regulation of general translation [46].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Ron D Harding HP Mathews M Sonenberg N Hershey JWB eIF2α phosphorylation in celluar stress responses and disease In translational control in biology and medicine 2007 New York Cold Spring Harbor Laboratory Press 345 68

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    TSC1 and TSC2 are negative regulators of mTOR phosphorylation by blocking the small GTPase Rheb activity.

    “Recently, it has been demonstrated that two tumour suppressor genes, the tuberous sclerosis complex (TSC) gene TSC1 (or Hamartin) and TSC2 (or Tuberin) were negative regulators of mTOR phosphorylation [78] by blocking the small GTPase Rheb activity, which is a positive regulator of mTOR [79, 80].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [78] Krymskaya VP Tumour suppressors hamartin and tuberin: intracellular signalling Cell Signal 2003 15 729 39 12781866 source
    • cites [79] Long X Lin Y Ortiz-Vega S Rheb binds and regulates the mTOR kinase Curr Biol 2005 15 702 13 15854902 source
    • cites [80] Manning BD Cantley LC Rheb fills a GAP between TSC and TOR Trends Biochem Sci 2003 28 573 6 14607085 source

  • May combine two claims.

    Interpretationreasoning

    PKR could be an early biomarker of neuronal death and a critical target for a therapeutic programme in AD.

    “PKR could be an early biomarker of the neuronal death and a critical target for a therapeutic programme in AD.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The molecular and cellular alterations measured in peripheral lymphocytes reflect the same disease processes occurring in the AD brain sufficiently to serve as biomarkers.
    • Rests on an assumption: PKR activation is a cause, not merely a consequence, of the neurodegenerative cascade in AD.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Different types of T cells would be expected to have different effects on microglial cell activation and therefore on amyloid clearance.

    “Different types of T cells would be expected to have different effects on microglial cell activation and therefore on amyloid clearance.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    CXCR2 is associated with T-cell adhesion on brain endothelia and transendothelial migration.

    “Furthermore, recent evidence revealed that peripheral T cells of AD patients overexpressed CXCR2 (CXC chemokine receptor 2), which is intracerebral microglial TNF-α-dependent and is associated with T-cell adhesion on brain endothelia and transendothelial migration [167].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [167] Liu YJ Guo DW Tian L Peripheral T cells derived from Alzheimer's disease patients overexpress CXCR2 contributing to its transendothelial migration, which is microglial TNF-alpha-dependent Neurobiol Aging 2008 DOI: 10.1016/j.neurobiolaging.2008.03.024 18462836 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The interaction of CD40 on microglia and CD40L on T cells promotes pro-inflammatory microglial cell activation in response to Aβ.

    “A study has shown that the interaction of CD40 (expressed on the surface of microglia) and CD40L (T-cell receptor) promotes pro-inflammatory microglial cell activation in response to Aβ[166].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [166] Tan J Town T Crawford F Role of CD40 ligand in amyloidosis in transgenic Alzheimer's mice Nat Neurosci 2002 5 1288 93 12402041 source

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing), S4 (based).

    Interpretationreasoning

    Expression of conformationally altered p53 could confer a higher resistance to the activated PKR signalling pathway.

    “First, expression of the conformationaly altered p53 could confer a higher resistance to the activated PKR signalling pathway.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The molecular and cellular alterations measured in peripheral lymphocytes reflect the same disease processes occurring in the AD brain sufficiently to serve as biomarkers.

  • May combine two claims.

    Interpretationreasoning

    PKR seems to be the initiator of this deregulation which could be involved in the failure of the re-entry of neurons in cell cycle.

    “PKR seems to be the initiator of this deregulation which could be involved in the failure of the re-entry of neurons in cell cycle.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: PKR activation is a cause, not merely a consequence, of the neurodegenerative cascade in AD.

  • May combine two claims.

    Premisecitation

    PKR is physically associated with p53 and phosphorylated it in mouse embryo fibroblasts cells treated with IFN.

    “It is known that PKR is physically associated with p53 and phosphorylated it in mouse embryo fibroblasts cells treated with IFN [64].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [64] Cuddihy AR Wong AH Tam NW The double-stranded RNA activated protein kinase PKR physically associates with the tumor suppressor p53 protein and phosphorylates human p53 on serine 392 in vitro Oncogene 1999 18 2690 702 10348343 source

  • May combine two claims.

    Premisecitation

    mTOR suppresses caspase-1 activation and orchestrates the defence programme of innate immune cells.

    “Third, mTOR suppresses caspase-1 activation and orchestrates the defence programme of innate immune cells [149].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [149] Schmitz F Heit A Dreher S Mammalian target of rapamycin (mTOR) orchestrates the defense program of innate immune cells Eur J Immunol 2008 38 2981 92 18924132 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Inflammatory mechanisms represent an important component which first contribute to defence mechanisms but secondly, stimulated by degeneration, may significantly contribute to disease progression and chronicity.

    “Finally, inflammatory mechanisms represent an important component which, first contribute to defence mechanisms but secondly, stimulated by degeneration, may significantly contribute to disease progression and chronicity [15, 150, 151].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [15] Heneka MT O’Banion MK Inflammatory processes in Alzheimer's disease J Neuroimmunol 2007 184 69 91 17222916 source
    • cites [150] Wyss-Coray T Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat Med 2006 12 1005 15 16960575 source
    • cites [151] Wyss-Coray T Mucke L Inflammation in neurodegenerative disease – a double-edged sword Neuron 2002 35 419 32 12165466 source

  • May combine two claims.

    Interpretationreasoning

    Statistical correlations between proteins and genes suggest that active PKR could phosphorylate p53, which could induce the transcription of Redd1 gene.

    “Furthermore, statistical correlations between proteins and genes suggest that active PKR could phosphorylate p53, which could induce the transcription of Redd1 gene.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Blockade of TNF-α production at the periphery prevented histological lesions induced by IL-1β in CNS.

    “Recently, it was demonstrated that a blockade of TNF-α production at the periphery prevented histological lesions induced by IL-1β in CNS [157].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [157] Jiang Y Deacon R Anthony DC Inhibition of peripheral TNF can block the malaise associated with CNS inflammatory diseases Neurobiol Dis 2008 32 125 32 18672064 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Endogenous Redd1 is induced following energy stress and inhibition of endogenous Redd1 increases cell size in a rapamycin-sensitive manner.

    “Data demonstrated that endogenous Redd1 is induced following energy stress and inhibition of endogenous Redd1 increases cell size in a rapamycin-sensitive manner [111].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [111] Sofer A Lei K Johannessen CM Regulation of mTOR and cell growth in response to energy stress by REDD1 Mol Cell Biol 2005 25 5834 45 15988001 PMC1168803 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Systemic immune response, including T-cell immune response, may be involved in the inflammation process of AD.

    “increased studies suggest that systemic immune response, including T-cell immune response, may be involved in the inflammation process of AD [152, 153].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [152] Miscia S Ciccocioppo F Lanuti P Abeta(1–42) stimulated T cells express P-PKC-delta and P-PKC-zeta in Alzheimer disease Neurobiol Aging 2009 30 394 406 17850925 source
    • cites [153] Town T Tan J Flavell RA T-cells in Alzheimer's disease Neuromolecular Med 2005 7 255 64 16247185 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    CXCR2 is intracerebral microglial TNF-α-dependent.

    “Furthermore, recent evidence revealed that peripheral T cells of AD patients overexpressed CXCR2 (CXC chemokine receptor 2), which is intracerebral microglial TNF-α-dependent and is associated with T-cell adhesion on brain endothelia and transendothelial migration [167].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [167] Liu YJ Guo DW Tian L Peripheral T cells derived from Alzheimer's disease patients overexpress CXCR2 contributing to its transendothelial migration, which is microglial TNF-alpha-dependent Neurobiol Aging 2008 DOI: 10.1016/j.neurobiolaging.2008.03.024 18462836 source

  • May combine two claims.

    Premisecitation

    Ray et al. found 18 signalling proteins in blood plasma that can be used to classify blinded samples from Alzheimer's and control patients with close to 90% accuracy and to identify patients with mild cognitive impairment that progressed to AD 2-6 years later.

    “Ray et al.[145] have found 18 signalling proteins in blood plasma that can be used to classify blinded samples from Alzheimer's and control patients with close to 90% accuracy and to identify patients with mild cognitive impairment that progressed to AD 2–6 years later.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [145] Ray S Britschgi M Herbert C Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins Nat Med 2007 13 1359 62 17934472 source

  • May combine two claims.

    Interpretationnone given

    In peripheral mononuclear cells of Alzheimer's disease patients, PKR can control the cell cycle and the inflammatory reaction.

    “In the brain, this disturbance is associated with the neuronal death while in peripheral mononuclear cells of AD patients, PKR can control the cell cycle and the inflammatory reaction.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: PKR controls the cell cycle, the proliferation and differentiation of cells.

  • May combine two claims.

    Premisecitation

    In brains of APPslPS1 KI mice, levels of phosphorylated PKR were significantly increased as early as 3 months of age, associated with intraneuronal amyloid peptide, before the massive neuronal death observed at 6 months.

    “We can remember that the levels of phosphorylated PKR were significantly increased in brains of APPslPS1 KI mice as early as 3 months of age associated with intraneuronal amyloid peptide before the massive neuronal death observed at 6 months [97].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [97] Page G Rioux Bilan A Ingrand S Activated double-stranded RNA-dependent protein kinase and neuronal death in models of Alzheimer's disease Neuroscience 2006 139 1343 54 16581193 source

  • May combine two claims.

    Interpretationcitation

    NF-κB could be under the control of PKR in Alzheimer's disease because NF-κB is activated in Alzheimer's disease.

    “However, NF-κB could be under the control of PKR in AD because this factor is activated in AD [177, 178].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [177] Fontalba A Gutierrez O Llorca J Deficiency of CARD8 is associated with increased Alzheimer's disease risk in women Dement Geriatr Cogn Disord 2008 26 247 50 18841008 source
    • cites [178] Paris D Patel N Quadros A Inhibition of Abeta production by NF-kappaB inhibitors Neurosci Lett 2007 415 11 6 17223266 source

  • May combine two claims.

    Interpretationreasoning

    PKR may not be a biomarker of cognitive decline but rather an early biomarker of cell death.

    “So, PKR may not be a biomarker of cognitive decline but rather an early biomarker of cell death.”
    Quote in the paperSubstantial claim
41 of 41

  • The paper relies on this without support.

    The molecular and cellular alterations measured in peripheral lymphocytes reflect the same disease processes occurring in the AD brain sufficiently to serve as biomarkers.

    “The control of translation through PKR/eIF2a signalling pathway is altered in AD lymphocytes as it was observed in brains of AD patients [50, 95].”
    “Thus, peripheral cell's biomarkers, easily accessible, could facilitate an early diagnosis or help following the severity of disease.”

  • The paper relies on this without support.

    PKR activation is a cause, not merely a consequence, of the neurodegenerative cascade in AD.

    “PKR seems to be the initiator of this deregulation which could be involved in the failure of the re-entry of neurons in cell cycle.”
    “The inhibition of PKR activity may represent an effective therapeutic strategy in the treatment of AD.”

  • The paper relies on this without support.

    The molecular link p53/Redd1/TSC2 operates in human AD brain as it does in cell models.

    “p53, Redd1 and TSC2 can be molecular links between the up-regulation of PKR and the down-regulation of mTOR largely described in AD (Fig. 2).”
    “In addition, we reported that PKR represents an initiator of deregulated translation via two consecutive targets p53 and Redd1 in AD lymphocytes [102].”

  • The paper relies on this without support.

    PKR is a constitutive protein.

    “However, PKR is a constitutive protein and all its physiological roles are yet unknown.”

  • The paper relies on this without support.

    PKR controls the cell cycle, the proliferation and differentiation of cells.

    “Besides its role in the antiviral defence mechanism of the host, PKR controls the cell cycle, the proliferation and differentiation of cells.”
5 of 5

Cites

Flagged first, then by citations

Research works printed but not linked: 4

  1. Hinnebusch AG, 2007, In translational control in biology and medicine, 225
  2. Ron D, 2007, In translational control in biology and medicine, 345
  3. Raught B, 2007, In translational control in biology and medicine, 369
  4. 10.1038/sj.mp.4002060 · DOI

Cited by

Sorted by citations

Related

Authors
Morel, M., Couturier, J., Lafay‐Chebassier, C., Paccalin, M., & Page, G.
Affiliations
  • Université de Poitiers (FR)
  • Inserm (FR)
Corresponding author
Page, Guylène
ORCID
Venue
Journal of Cellular and Molecular Medicine
Publisher
Wiley
Published
2009-08
Volume
13
Issue
8a
Pages
1476-1488
ISSN
  • 1582-1838 (ISSN-L)
  • 1582-4934
DOI
10.1111/j.1582-4934.2009.00849.x
PMC
PMC3828860
OpenAlex
W1994047469
Cited by
47
References
179
Citations by year
2026: 2 · 2025: 2 · 2024: 2 · 2023: 1 · 2022: 2 · 2021: 3 · 2020: 4 · 2019: 1 · 2017: 1 · 2016: 5 · 2015: 4 · 2014: 3 · 2013: 6 · 2012: 5
FWCI
2.16
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Journal of Cellular and Molecular Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (submittedVersion)
  • PubMed Central (submittedVersion)
  • DIAL (Catholic University of Leuven) (submittedVersion, other-oa)
Funders
Centre Hospitalier Universitaire de Poitiers
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
Keywords
PKR, double-stranded RNA-dependent protein kinase, Alzheimer's disease, mTOR signaling, eIF2α, eIF2, eIF4E, translational regulation, amyloid-beta, neurofibrillary tangles, p53, Rpd3, TSC2, lymphocytes, cognitive impairment, biomarkers, neuronal cell death
MeSH terms
Alzheimer Disease, Animals, Humans, Protein Biosynthesis, Signal Transduction, Biomarkers, Protein Serine-Threonine Kinases, eIF-2 Kinase, Intracellular Signaling Peptides and Proteins, TOR Serine-Threonine Kinases

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-27.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-27.

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