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Cited by 190Alzheimer's disease research and treatmentsPI3K/AKT/mTOR signaling in cancerDementia and Cognitive Impairment Research

mTOR‐dependent signalling in Alzheimer's disease

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Pei, Jin‐Jing, Hugon, Jacques·2008·Journal of Cellular and Molecular Medicine
DOI 10.1111/j.1582-4934.2008.00509.xPMC PMC3828871
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Abstract

Introduction Neurodegeneration and neurofibrillary degeneration in Alzheimer's disease brains Dysfunction of protein synthesis mediated by mTOR‐dependent signalling in Alzheimer's disease brains Neurodegeneration mediated by mTOR‐dependent signalling Tau phosphorylation mediated by mTOR‐dependent signalling mTOR‐dependent signalling in lymphocytes of AD: potential biomarkers for AD diagnosis mTOR‐dependent signalling and other neurodegenerative diseases Perspectives Conclusions Neurodegeneration and neurofibrillary degeneration are the two main pathological mechanisms of cognitive impairments in Alzheimer's disease (AD). It is not clear what factors determine the fates of neurons during the progress of the disease. Emerging evidence has suggested that mTOR‐dependent signalling is involved in the two types of degeneration in AD brains. This review focuses on the roles of mTOR‐dependent signalling in the pathogenesis of AD. It summarizes the recent advancements in the understanding of its roles in neu‐rodegeneration and neurofibrillary degeneration, as well as the evidence achieved when mTOR‐related signalling components were tested as potential biomarkers of cognitive impairments in the clinical diagnosis of AD.

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  • Dysregulated mTORC1 signaling is implicated in epilepsy, Alzheimer's disease, and autism spectrum disorder.

    “Dysregulated mTORC1 signaling is implicated in many neurological disorders such as epilepsy, Alzheimer's disease (AD), and autism spectrum disorder (ASD) (11,12).”

    From Analysis of proteins that rapidly change upon mechanistic/mammalian target of rapamycin complex 1 (mTORC1) repression identifies parkinson protein 7 (PARK7) as a novel protein aberrantly expressed in tuberous sclerosis complex (TSC) (2016) · cites this paper as [11]

    The Perspectives section (page unavailable) implicates altered mTOR-dependent signalling in Alzheimer’s disease, and the Introduction identifies mTORC1 as a distinct mTOR complex. The cited paper does not address epilepsy or autism spectrum disorder, so it supports only the Alzheimer’s disease portion of the attributed claim. (LLM, conf=0.88)

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  • 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].”

    From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [94]

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  1. [1]Tee AR Blenis J Proud CG Analysis of mTOR signaling by the small G-proteins, Rheb and RhebL1 FEBS Lett 2005 579 4763 8 16098514
  2. [2]Siekierka JJ Hung SH Poe M Lin CS Sigal NH A cytosolic binding protein for the immunosuppressant FK506 has peptidyl-prolyl isomerase activity but is distinct from cyclophilin Nature 1989 341 755 7 2477714
  3. [4]Bhaskar PT Hay N The two TORCs and Akt Dev Cell 2007 12 487 502 17419990
  4. [5]Kim DH Sarbassov DD Ali SM King JE Latek RR Erdjument-Bromage H Tempst P Sabatini DM mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery Cell 2002 110 163 75 12150925
  5. [6]Wullschleger S Loewith R Oppliger W Hall MN Molecular organization of target of rapamycin complex 2 J Biol Chem 2005 280 30697 704 16002396
  6. [7]Reiling JH Sabatini DM Increased mTORC1 signaling UPRegulates stress Mol Cell 2008 29 533 5 18342598
  7. [9]Wullschleger S Loewith R Hall MN TOR signaling in growth and metabolism Cell 2006 124 471 84 16469695
  8. [10]Jacinto E Hall MN Tor signalling in bugs, brain and brawn Nat Rev Mol Cell Biol 2003 4 117 26 12563289
  9. [11]Kwon CH Zhu X Zhang J Baker SJ mTor is required for hypertrophy of Pten-deficient neuronal soma in vivo Proc Natl Acad Sci USA 2003 100 12923 8 14534328 PMC240720
  10. [12]Jaworski J Sheng M The growing role of mTOR in neuronal development and plasticity Mol Neurobiol 2006 34 205 19 17308353
  11. [13]Zhou XW Li X Bjorkdahl C Sjogren MJ Alafuzoff I Soininen H Grundke-Iqbal I Iqbal K Winblad B Pei JJ Assessments of the accumulation severities of amyloid beta-protein and hyperphosphorylated tau in the medial temporal cortex of control and Alzheimer's brains Neurobiol Dis 2006 22 657 68 16513361
  12. [14]Dickson DW Apoptotic mechanisms in Alzheimer neurofibrillary degeneration: cause or effect? J Clin Invest 2004 114 23 7 15232608 PMC437977
  13. [15]Lafay-Chebassier C Perault-Pochat MC Page G Rioux Bilan A Damjanac M Pain S Houeto JL Gil R Hugon J The immunosuppressant rapamycin exacerbates neurotoxicity of Abeta peptide J Neurosci Res 2006 84 1323 34 16955484
  14. [16]Zhou XW Gustafsson JA Tanila H Bjorkdahl C Liu R Winblad B Pei JJ Tau hyperphosphorylation correlates with reduced methylation of protein phos-phatase 2A Neurobiol Dis 2008 31 386 94 18586097
  15. [18]Langstrom N Eriksson A Winblad B Wallace W Translational control of gene expression in the human brain Prog Neuropsychopharmacol Biol Psychiatry 1989 13 469 79 2664896
  16. [19]Sajdel-Sulkowska EM Marotta CA Alzheimer's disease brain: alterations in RNA levels and in a ribonuclease-inhibitor complex Science 1984 225 947 9 6206567
  17. [20]Onuki R Bando Y Suyama E Katayama T Kawasaki H Baba T Tohyama M Taira K An RNA-dependent protein kinase is involved in tunicamycin-induced apoptosis and Alzheimer's disease EMBO J 2004 23 959 68 14765129 PMC380987
  18. [21]Peel AL Bredesen DE Activation of the cell stress kinase PKR in Alzheimer's disease and human amyloid precursor protein transgenic mice Neurobiol Dis 2003 14 52 62 13678666
  19. [23]An WL Cowburn RF Li L Braak H Alafuzoff I Iqbal K Grundke-Iqbal I Winblad B Pei JJ Up-regulation of phos-phorylated/activated p70 S6 kinase and its relationship to neurofibrillary pathology in Alzheimer's disease Am J Pathol 2003 163 591 607 12875979 PMC1868198
  20. [24]Chang RC Suen KC Ma CH Elyaman W Ng HK Hugon J 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
  21. [25]Suen KC Yu MS So KF Chang RC Hugon J 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
  22. [26]Page G Rioux Bilan A Ingrand S Lafay-Chebassier C Pain S Perault Pochat MC Bouras C Baye T Hugon J Activated double-stranded RNA-dependent protein kinase and neuronal death in models of Alzheimer's disease Neuroscience 2006 139 1343 54 16581193
  23. [27]Li X An WL Alafuzoff I Soininen H Winblad B Pei JJ Phosphorylated eukaryotic translation factor 4E is elevated in Alzheimer brain Neuroreport 2004 15 2237 40 15371741
  24. [30]Paschen W Djuricic B Mies G Schmidt-Kastner R Linn F Lactate and pH in the brain: association and dissociation in different pathophysiological states J Neurochem 1987 48 154 9 3794696
  25. [31]Clauberg M Joshi JG Regulation of serine protease activity by aluminum: implications for Alzheimer disease Proc Natl Acad Sci USA 1993 90 1009 12 7679214 PMC45800
  26. [32]Dorovkov MV Pavur KS Petrov AN Ryazanov AG Regulation of elongation factor-2 kinase by pH Biochemistry 2002 41 13444 50 12416990
  27. [33]Liu R Pei JJ Wang XC Zhou XW Tian Q Winblad B Wang JZ Acute anoxia induces tau dephosphorylation in rat brain slices and its possible underlying mechanisms J Neurochem 2005 94 1225 34 15992372
  28. [34]Wen Y Yang S Liu R Brun-Zinkernagel AM Koulen P Simpkins JW Transient cerebral ischemia induces aberrant neuronal cell cycle re-entry and Alzheimer's disease-like tauopathy in female rats J Biol Chem 2004 279 22684 92 14982935
  29. [35]Yates CM Butterworth J Tennant MC Gordon A Enzyme activities in relation to pH and lactate in postmortem brain in Alzheimer-type and other dementias J Neurochem 1990 55 1624 30 2213015
  30. [36]Langstrom NS Anderson JP Lindroos HG Winblad B Wallace WC Alzheimer's disease-associated reduction of polysomal mRNA translation Brain Res Mol Brain Res 1989 5 259 69 2747450
  31. [37]Ding Q Markesbery WR Chen Q Li F Keller JN Ribosome dysfunction is an early event in Alzheimer's disease J Neurosci 2005 25 9171 5 16207876 PMC6725754
  32. [38]Shenton D Smirnova JB Selley JN Carroll K Hubbard SJ Pavitt GD Ashe MP Grant CM Global translational responses to oxidative stress impact upon multiple levels of protein synthesis J Biol Chem 2006 281 29011 21 16849329
  33. [40]Smirnova JB Selley JN Sanchez-Cabo F Carroll K Eddy AA McCarthy JE Hubbard SJ Pavitt GD Grant CM Ashe MP Global gene expression profiling reveals widespread yet distinctive translational responses to different eukaryotic translation initiation factor 2B-targeting stress pathways Mol Cell Biol 2005 25 9340 9 16227585 PMC1265828
  34. [41]Preiss T Baron-Benhamou J Ansorge W Hentze MW Homodirectional changes in transcriptome composition and mRNA translation induced by rapamycin and heat shock Nat Struct Biol 2003 10 1039 47 14608375
  35. [43]Rogaeva E Kawarai T George-Hyslop PS Genetic complexity of Alzheimer's disease: successes and challenges J Alzheimers Dis 2006 9 381 7 16914876
  36. [44]Boutajangout A Boom A Leroy K Brion J P Expression of tau mRNA and soluble tau isoforms in affected and non-affected brain areas in Alzheimer's disease FEBS Lett 2004 576 183 9 15474035
  37. [45]Chambers CB Lee JM Troncoso JC Reich S Muma NA Overexpression of four-repeat tau mRNA isoforms in progressive supranuclear palsy but not in Alzheimer's disease Ann Neurol 1999 46 325 32 10482263
  38. [46]Mah VH Eskin TA Kazee AM Lapham L Higgins GA In situ hybridization of calcium/calmodulin dependent protein kinase II and tau mRNAs; species differences and relative preservation in Alzheimer's disease Brain Res Mol Brain Res 1992 12 85 94 1312209
  39. [47]Pearson RB Dennis PB Han JW Williamson NA Kozma SC Wettenhall RE Thomas G The principal target of rapamycin-induced p70s6k inactivation is a novel phosphorylation site within a conserved hydrophobic domain EMBO J 1995 14 5279 87 7489717 PMC394637
  40. [48]An WL Bjorkdahl C Liu R Cowburn RF Winblad B Pei JJ Mechanism of zinc-induced phosphorylation of p70 S6 kinase and glycogen synthase kinase 3beta in SH-SY5Y neuroblastoma cells J Neurochem 2005 92 1104 15 15715661
  41. [49]Lafay-Chebassier C Paccalin M Page G Barc-Pain S Perault-Pochat MC Gil R Pradier L Hugon J 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
  42. [50]Björkdahl C Tau and neurofilament proteins in Alzheimer's disease and related cell models Thesis 2007 Karolinska Institutet
  43. [51]Pei JJ Gong CX An WL Winblad B Cowburn RF Grundke-Iqbal I Iqbal K Okadaic-acid-induced inhibition of protein phosphatase 2A produces activation of mitogen-activated protein kinases ERK1/2, MEK1/2, and p70 S6, similar to that in Alzheimer's disease Am J Pathol 2003 163 845 58 12937126 PMC1868262
  44. [52]An WL Role of p70 S6 kinase in the formation of tau pathogenesis in Alzheimer's disease Thesis 2005 Karolinska Institutet
  45. [53]Meske V Albert F Ohm TG Coupling of mammalian target of rapamycin with phosphoinositide 3-kinase signaling pathway regulates protein phosphatase 2A-and glycogen synthase kinase-3 -dependent phosphorylation of Tau J Biol Chem 2008 283 100 9 17971449
  46. [54]Pei JJ An WL Zhou XW Nishimura T Norberg J Benedikz E Gotz J Winblad B P70 S6 kinase mediates tau phosphory-lation and synthesis FEBS Lett 2006 580 107 14 16364302
  47. [55]Virdee K Yoshida H Peak-Chew S Goedert M Phosphorylation of human microtubule-associated protein tau by protein kinases of the AGC subfamily FEBS Lett 2007 581 2657 62 17512525
  48. [56]Zhou XW Tanila H Pei JJ Parallel increase in p70 kinase activation and tau phosphorylation (S262) with Abeta overproduction FEBS Lett 2008 582 159 64 18068129
  49. [57]Paccalin M Pain-Barc S Pluchon C Paul C Bazin H Gil R Hugon J The relation between p70S6k expression in lymphocytes and the decline of cognitive test scores in patients with Alzheimer disease Arch Intern Med 2005 165 2428 9 16287775
  50. [58]Paccalin M Al Khidir F Barc SP Pluchon C Perrault-Pochat MC Gil R Hugon J Peripheral p70S6k levels and emotional memory in patients with Alzheimer's disease Neurosci Lett 2006 410 162 4 17101223
  51. [59]Paccalin M Pain-Barc S Pluchon C Paul C Besson MN Carret-Rebillat AS Rioux-Bilan A Gil R Hugon J 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
  52. [60]Morimoto N Nagai M Ohta Y Miyazaki K Kurata T Morimoto M Murakami T Takehisa Y Ikeda Y Kamiya T Abe K Increased autophagy in transgenic mice with a G93A mutant SOD1 gene Brain Res 2007 1167 112 7 17689501
  53. [61]Malagelada C Ryu EJ Biswas SC Jackson-Lewis V Greene LA RTP801 is elevated in Parkinson brain substantia nigral neurons and mediates death in cellular models of Parkinson's disease by a mechanism involving mammalian target of rapamycin inactivation J Neurosci 2006 26 9996 10005 17005863 PMC6674487
  54. [63]Chen L Liu L Luo Y Huang S MAPK and mTOR pathways are involved in cadmium-induced neuronal apoptosis J Neurochem 2008 105 251 61 18021293
  55. [64]Wu X Reiter CE Antonetti DA Kimball SR Jefferson LS Gardner TW Insulin promotes rat retinal neuronal cell survival in a p70S6K-dependent manner J Biol Chem 2004 279 9167 75 14660591
  56. [65]Vogt BA Van Hoesen GW Vogt LJ Laminar distribution of neuron degeneration in posterior cingulate cortex in Alzheimer's disease Acta Neuropathol 1990 80 581 9 1703381
  57. [66]Lesort M Blanchard C Yardin C Esclaire F Hugon J Cultured neurons expressing phosphorylated tau are more resistant to apoptosis induced by NMDA or serum deprivation Brain Res Mol Brain Res 1997 45 127 32 9105678
  58. [67]Yardin C Terro F Lesort M Esclaire F Hugon J FK506 antagonizes apoptosis and c-jun protein expression in neuronal cultures Neuroreport 1998 9 2077 80 9674596
  59. [68]Elyaman W Terro F Suen KC Yardin C Chang RC Hugon J BAD and Bcl-2 reguation are early events linking neuronal endoplasmic reticulum stress to mitochondria-mediated apoptosis Brain Res Mol Brain Res 2002 109 233 8 12531534
  60. [69]Mills JC Lee VM Pittman RN Activation of a PP2A-like phosphatase and dephosphorylation of tau protein characterize onset of the execution phase of apoptosis J Cell Sci 1998 111 625 36 9454736

Cited by

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Authors
Pei, J., & Hugon, J.
Affiliations
  • Karolinska Institutet (SE)
  • Inserm (FR)
Corresponding author
Pei, Jin‐Jing
ORCID
Hugon, Jacques
Venue
Journal of Cellular and Molecular Medicine
Publisher
Wiley
Published
2008-12-02
Volume
12
Issue
6b
Pages
2525-2532
ISSN
  • 1582-1838 (ISSN-L)
  • 1582-4934
DOI
10.1111/j.1582-4934.2008.00509.x
PMC
PMC3828871
OpenAlex
W1984295096
Cited by
190
References
8
Citations by year
2026: 1 · 2025: 8 · 2024: 8 · 2023: 10 · 2022: 13 · 2021: 10 · 2020: 11 · 2019: 10 · 2018: 12 · 2017: 18 · 2016: 16 · 2015: 8 · 2014: 14 · 2013: 9 · 2012: 20
FWCI
0.80
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Journal of Cellular and Molecular Medicine (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Styrelsen för Internationellt Utvecklingssamarbete
  • Gun och Bertil Stohnes Stiftelse
  • Institut National de la Santé et de la Recherche Médicale
  • University of Hong Kong
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, mTOR signaling, neurodegeneration, neurofibrillary degeneration, tau phosphorylation, protein synthesis, lymphocytes, biomarkers, cognitive impairment, neurodegenerative diseases
MeSH terms
Alzheimer Disease, Animals, Humans, Nerve Degeneration, Protein Kinases, Protein Biosynthesis, Signal Transduction, tau Proteins, TOR Serine-Threonine Kinases

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