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Cited by 154Alzheimer's disease research and treatmentsProtein Kinase Regulation and GTPase SignalingCholinesterase and Neurodegenerative Diseases

Modulation of Statin-Activated Shedding of Alzheimer APP Ectodomain by ROCK

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Pedrini, Steve, Carter, Troy L, Prendergast, George, Petanceska, Suzana, Ehrlich, Michelle E, Gandy, Sam·2005·PLoS Medicine
DOI 10.1371/journal.pmed.0020018PMC PMC543463
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Abstract

BACKGROUND: Statins are widely used cholesterol-lowering drugs that act by inhibiting HMGCoA reductase, the rate-limiting enzyme in cholesterol biosynthesis. Recent evidence suggests that statin use may be associated with a decreased risk for Alzheimer disease, although the mechanisms underlying this apparent risk reduction are poorly understood. One popular hypothesis for statin action is related to the drugs' ability to activate alpha-secretase-type shedding of the alpha-secretase-cleaved soluble Alzheimer amyloid precursor protein ectodomain (sAPP(alpha)). Statins also inhibit the isoprenoid pathway, thereby modulating the activities of the Rho family of small GTPases-Rho A, B, and C-as well as the activities of Rac and cdc42. Rho proteins, in turn, exert many of their effects via Rho-associated protein kinases (ROCKs). Several cell-surface molecules are substrates for activated alpha-secretase-type ectodomain shedding, and regulation of shedding typically occurs via activation of protein kinase C or extracellular-signal-regulated protein kinases, or via inactivation of protein phosphatase 1 or 2A. However, the possibility that these enzymes play a role in statin-stimulated shedding has been excluded, leading us to investigate whether the Rho/ROCK1 protein phosphorylation pathway might be involved. METHODS AND FINDINGS: We found that both atorvastatin and simvastatin stimulated sAPP(alpha) shedding from a neuroblastoma cell line via a subcellular mechanism apparently located upstream of endocytosis. A farnesyl transferase inhibitor also increased sAPP(alpha) shedding, as did a dominant negative form of ROCK1. Most conclusively, a constitutively active ROCK1 molecule inhibited statin-stimulated sAPP(alpha) shedding. CONCLUSION: Together, these data suggest that statins exert their effects on shedding of sAPP(alpha) from cultured cells, at least in part, by modulation of the isoprenoid pathway and ROCK1.

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  • Several studies have demonstrated that statin-mediated RhoA/ROCK inhibition reduces NFT formation and decreases Aβ production.

    “Indeed, several studies have demonstrated that statin-mediated RhoA/ROCK inhibition reduces NFT formation and decreases Aβ production [182,183,187,224].”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [182]

    The Introduction (page unavailable) reports that statins decrease Aβ release in cultured rat hippocampal neurons, and the Discussion links statin-activated APP shedding in cultured cells to Rho/ROCK signaling. The paper does not report reduced NFT formation, nor does it demonstrate that RhoA/ROCK inhibition causes the reported decrease in Aβ release. (LLM, conf=0.86)

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Research works printed but not linked: 68

  1. Gandy S Martins RN Buxbaum J Molecular and cellular basis for anti-amyloid therapy in Alzheimer disease Alzheimer Dis Assoc Disord 2003 17 259 66 14657791
  2. Buxbaum JD Liu KN Luo Y Slack JL Stocking KL Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor J Biol Chem 1998 273 27765 27767 9774383
  3. Sisodia SS Beta-amyloid precursor protein cleavage by a membrane-bound protease Proc Natl Acad Sci U S A 1992 89 6075 6079 1631093 PMC49440
  4. Caporaso GL Gandy SE Buxbaum JD Ramabhadran TV Greengard P Protein phosphorylation regulates secretion of Alzheimer beta/A4 amyloid precursor protein Proc Natl Acad Sci U S A 1992 89 3055 3059 1557413 PMC48802
  5. Gillespie SL Golde TE Younkin SG Secretory processing of the Alzheimer amyloid beta/A4 protein precursor is increased by protein phosphorylation Biochem Biophys Res Commun 1992 187 1285 1290 1417805
  6. Jick H Zornberg GL Jick SS Seshadri S Drachman DA Statins and the risk of dementia Lancet 2000 356 1627 1631 11089820
  7. Wolozin B Kellman W Ruosseau P Celesia GG Siegel G Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors Arch Neurol 2000 57 1439 1443 11030795
  8. Yaffe K Barrett-Connor E Lin F Grady D Serum lipoprotein levels, statin use, and cognitive function in older women Arch Neurol 2002 59 378 384 11890840
  9. Rockwood K Kirkland S Hogan DB MacKnight C Merry H Use of lipid-lowering agents, indication bias, and the risk of dementia in community-dwelling elderly people Arch Neurol 2002 59 223 227 11843693
  10. Fassbender K Simons M Bergmann C Stroick M Lutjohann D Simvastatin strongly reduces levels of Alzheimer's disease beta-amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo Proc Natl Acad Sci U S A 2001 98 5856 5861 11296263 PMC33303
  11. Petanceska SS DeRosa S Olm V Diaz N Sharma A Statin therapy for Alzheimer's disease: Will it work? J Mol Neurosci 2002 19 155 161 12212773
  12. Simons M Keller P De Strooper B Beyreuther K Dotti CG Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons Proc Natl Acad Sci U S A 1998 95 6460 6464 9600988 PMC27798
  13. Kojro E Gimpl G Lammich S Marz W Fahrenholz F Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the alpha-secretase ADAM 10 Proc Natl Acad Sci U S A 2001 98 5815 5820 11309494 PMC33296
  14. Parvathy S Ehrlich M Pedrini S Diaz N Refolo L Atorvastatin-induced activation of Alzheimer's alpha secretase is resistant to standard inhibitors of protein phosphorylation-regulated ectodomain shedding J Neurochem 2004 90 1005 1010 15287907
  15. Puglielli L Tanzi RE Kovacs D Alzheimer's disease: The cholesterol connection Nat Neurosci 2003 6 345 351 12658281
  16. Wolozin B Cholesterol and the biology of Alzheimer's disease Neuron 2004 41 7 10 14715130
  17. Zhang FL Casey PJ Protein prenylation: Molecular mechanisms and functional consequences Annu Rev Biochem 1996 65 241 269 8811180
  18. Ishizaki T Maekawa M Fujisawa K Okawa K Iwamatsu A The small GTP-binding protein Rho binds to and activates a 160 kDa Ser/Thr protein kinase homologous to myotonic dystrophy kinase EMBO J 1996 15 1885 1893 8617235 PMC450107
  19. Matsui T Amano M Yamamoto T Chihara K Nakafuku M Rho-associated kinase, a novel serine/threonine kinase, as a putative target for small GTP binding protein Rho EMBO J 1996 15 2208 2216 8641286 PMC450144
  20. Riento K Ridley AJ Rocks: Multifunctional kinases in cell behaviour Nat Rev Mol Cell Biol 2003 4 446 456 12778124
  21. Kimura K Ito M Amano M Chihara K Fukata Y Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase) Science 1996 273 245 248 8662509
  22. Ohashi K Nagata K Maekawa M Ishizaki T Narumiya S Rho-associated kinase ROCK1 activates LIM-kinase 1 by phosphorylation at threonine 508 within the activation loop J Biol Chem 2000 275 3577 3582 10652353
  23. Sumi T Matsumoto K Nakamura T Specific activation of LIM kinase 2 via phosphorylation of threonine 505 by ROCK, a Rho-dependent protein kinase J Biol Chem 2001 276 670 676 11018042
  24. Jeon S Kim S Park JB Suh PG Kim YS RhoA and Rho kinase-dependent phosphorylation of moesin at Thr-558 in hippocampal neuronal cells by glutamate J Biol Chem 2002 277 16576 16584 11867620
  25. Zhou Y Su Y Li B Liu F Ryder JW Nonsteroidal anti-inflammatory drugs can lower amyloidogenic Abeta42 by inhibiting Rho Science 2003 302 1215 1217 14615541
  26. Buxbaum JD Gandy SE Cicchetti P Ehrlich ME Czernik AJ Processing of Alzheimer beta/A4 amyloid precursor protein: Modulation by agents that regulate protein phosphorylation Proc Natl Acad Sci U S A 1990 87 6003 6006 2116015 PMC54458
  27. Ishizaki T Naito M Fujisawa K Maekawa M Watanabe N p160ROCK, a Rho-associated coiled-coil forming protein kinase, works downstream of Rho and induces focal adhesions FEBS Lett 1997 404 118 124 9119047
  28. Nakayama AY Harms MB Luo L Small GTPases Rac and Rho in the maintenance of dendritic spines and branches in hippocampal pyramidal neurons J Neurosci 2000 20 5329 5338 10884317 PMC6772334
  29. Thinakaran G Borchelt DR Lee MK Slunt HH Spitzer L Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo Neuron 1996 17 181 190 8755489
  30. Ehehalt R Keller P Haass C Thiele C Simons K Amyloidogenic processing of the Alzheimer beta-amyloid precursor protein depends on lipid rafts J Cell Biol 2003 160 113 123 12515826 PMC2172747
  31. Frenette PS Locking a leukocyte integrin with statins N Engl J Med 2001 345 1419 1421 11794177
  32. Pandiella A Massague J Cleavage of the membrane precursor for transforming growth factor alpha is a regulated process Proc Natl Acad Sci U S A 1991 88 1726 1730 2000380 PMC51097
  33. Bosenberg MW Pandiella A Massague J Activated release of membrane-anchored TGF-alpha in the absence of cytosol J Cell Biol 1993 122 95 101 8314849 PMC2119606
  34. Arribas J Massague J Transforming growth factor-alpha and beta-amyloid precursor protein share a secretory mechanism J Cell Biol 1995 128 433 441 7844156 PMC2120346
  35. Roβner S Fuchsbrunner K Lange-Dohna C Hartlage-Rubsamen M Bigl V Munc13–1-mediated vesicle priming contributes to secretory amyloid precursor protein processing J Biol Chem 2004 279 27841 27844 15123597
  36. Sisodia SS Koo EH Beyreuther K Unterbeck A Price DL Evidence that beta-amyloid protein in Alzheimer's disease is not derived by normal processing Science 1990 248 492 495 1691865
  37. Perez RG Soriano S Hayes JD Ostaszewski B Xia W Mutagenesis identifies new signals for beta-amyloid precursor protein endocytosis, turnover, and the generation of secreted fragments, including Abeta42 J Biol Chem 1999 274 18851 18856 10383380
  38. King GD Perez RG Steinhilb ML Gaut JR Turner RS X11alpha modulates secretory and endocytic trafficking and metabolism of amyloid precursor protein: Mutational analysis of the YENPTY sequence Neuroscience 2003 120 143 154 12849748
  39. Seabra MC Goldstein JL Sudhof TC Brown MS Rab geranylgeranyl transferase. A multisubunit enzyme that prenylates GTP-binding proteins terminating in Cys-X-Cys or Cys-Cys J Biol Chem 1992 267 14497 14503 1321151
  40. Weidemann A Konig G Bunke D Fischer P Salbaum JM Identification, biogenesis, and localization of precursors of Alzheimer's disease A4 amyloid protein Cell 1989 57 115 126 2649245
  41. de Celis JF Mari-Beffa M Garcia-Bellido A Cell-autonomous role of Notch, an epidermal growth factor homologue, in sensory organ differentiation in Drosophila Proc Natl Acad Sci U S A 1991 88 632 636 1899143 PMC50866
  42. Khvotchev M Sudhof TC Proteolytic processing of APP by secretases does not require cell-surface transport J Biol Chem 2004 279 47101 47108 15316009
  43. Hartmann D Tournoy J Saftig P Annaert W De Strooper B Implication of APP secretases in Notch signaling J Mol Neurosci 2001 17 171 181 11816790
  44. Gandy S Czernik AJ Greengard P Phosphorylation of Alzheimer disease amyloid precursor peptide by protein kinase C and Ca2+/calmodulin-dependent protein kinase II Proc Natl Acad Sci U S A 1988 85 6218 6221 3137567 PMC281937
  45. Oltersdorf T Ward PJ Henriksson T Beattie EC Neve R The Alzheimer amyloid precursor protein. Identification of a stable intermediate in the biosynthetic/degradative pathway J Biol Chem 1990 265 4492 4497 1968460
  46. Seubert P Oltersdorf T Lee MG Barbour R Blomquist C Secretion of beta-amyloid precursor protein cleaved at the amino terminus of the beta-amyloid peptide Nature 1993 361 260 263 7678698
  47. Felsenstein KM Ingalls KM Hunihan LW Roberts SB Reversal of the Swedish familial Alzheimer's disease mutant phenotype in cultured cells treated with phorbol 12,13-dibutyrate Neurosci Lett 1994 174 173 176 7970175
  48. Mattson MP Secreted forms of beta-amyloid precursor protein modulate dendrite outgrowth and calcium responses to glutamate in cultured embryonic hippocampal neurons J Neurobiol 1994 25 439 450 7915758
  49. Kamenetz F Tomita T Hsieh H Seabrook G Borchelt D APP processing and synaptic function Neuron 2003 37 925 937 12670422
  50. Zheng H Jiang M Trumbauer ME Hopkins R Sirinathsinghji DJ Mice deficient for the amyloid precursor protein gene Ann N Y Acad Sci 1996 777 421 426 8624124
  51. Heber S Herms J Gajic V Hainfellner J Aguzzi A Mice with combined gene knock-outs reveal essential and partially redundant functions of amyloid precursor protein family memebers J Neurosci 2000 20 7951 7963 11050115 PMC6772747
  52. Cao X Sudhof TC A transcriptionally active complex of APP with Fe65 and histone acetyltransferase Tip60 Science 2001 293 115 120 11441186
  53. Bodovitz S Klein WL Cholesterol modulates alpha-secretase cleavage of amyloid precursor protein J Biol Chem 1996 271 4436 4440 8626795
  54. Maillet M Robert SJ Cacquevel M Gastineau M Vivien D Crosstalk between Rap1 and Rac regulates secretion of sAPPalpha Nat Cell Biol 2003 5 633 639 12819788
  55. Kohl NE Omer CA Conner MW Anthony NJ Davide JP Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice Nat Med 1995 1 792 797 7585182
  56. Prendergast GC Actin' up: RhoB in cancer and apoptosis Nat Rev Cancer 2001 1 162 168 11905808
  57. da Cruz e Silva OA Iverfeldt K Oltersdorf T Sinha S Lieberburg I Regulated cleavage of Alzheimer beta-amyloid precursor protein in the absence of the cytoplasmic tail Neuroscience 1993 57 873 877 8309547
  58. Diaz-Rodriguez E Montero JC Esparis-Ogando A Yuste L Pandiella A Extracellular signal-regulated kinase phosphorylates tumor necrosis factor alpha-converting enzyme at threonine 735: A potential role in regulated shedding Mol Biol Cell 2002 13 2031 2044 12058067 PMC117622
  59. Xu H Greengard P Gandy S Regulated formation of Golgi secretory vesicles containing Alzheimer beta-amyloid precursor protein J Biol Chem 1995 270 23243 23245 7559474
  60. Skovronsky DM Lee VM Pratico D Amyloid precursor protein and amyloid beta peptide in human platelets. Role of cyclooxygenase and proteinkinase J Biol Chem 2001 276 17036 17043 11278299
  61. Skovronsky DM Moore DB Milla ME Doms RW Lee VM Protein kinase C-dependent alpha-secretase competes with beta-secretase for cleavage of amyloid-beta precursor protein in the trans-Golgi network J Biol Chem 2000 275 2568 2575 10644715
  62. Gandy S Greengard P Amyloidogenesis in Alzheimer's disease: Some possible therapeutic opportunities Trends Pharmacol Sci 1992 13 108 113 1574806
  63. Postina R Schroeder A Dewachter I Bohl J Schmitt U A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model J Clin Invest 2004 113 1456 1464 15146243 PMC406531
  64. Etcheberrigaray R Tan M Dewachter I Kuiperi C Van der Auwera I Therapeutic effects of PKC activators in Alzheimer's disease transgenic mice Proc Natl Acad Sci U S A 2004 101 11141 11146 15263077 PMC503753
  65. De Strooper B Konig G Alzheimer's disease: An inflammatory drug prospect Nature 2001 414 159 160 11700538
  66. Sparks DL Connor DJ Browne PJ Lopez JE Sabbagh MN HMG-CoA reductase inhibitors (statins) in the treatment of Alzheimer's disease and why it would be ill-advise to use one that crosses the blood-brain barrier J Nutr Health Aging 2002 6 324 331 12474023
  67. Heppner FL Gandy S McLaurin J Current concepts and future prospects for Alzheimer disease vaccines Alzheimer Dis Assoc Disord 2004 18 38 43 15195462
  68. Sjogren M Gustafsson K Syversen S Olsson A Edman A Treatment with simvastatin in patients with Alzheimer's disease lowers both alpha- and beta-cleaved amyloid precursor protein Dement Geriatr Cogn Disord 2003 16 25 30 12714796

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Authors
Pedrini, S., Carter, T. L., Prendergast, G., Petanceska, S., Ehrlich, M. E., & Gandy, S.
Affiliations
  • Thomas Jefferson University (US)
  • Lankenau Institute for Medical Research (US)
  • Nathan Kline Institute for Psychiatric Research (US)
Corresponding author
Gandy, Sam
ORCID
Venue
PLoS Medicine
Publisher
Public Library of Science (PLoS)
Published
2005-01-11
Volume
2
Issue
1
Pages
e18
ISSN
  • 1549-1277 (ISSN-L)
  • 1549-1676
DOI
10.1371/journal.pmed.0020018
PMC
PMC543463
OpenAlex
W1999607830
Cited by
154
References
2
Citations by year
2026: 2 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 5 · 2021: 2 · 2020: 5 · 2019: 5 · 2018: 6 · 2017: 4 · 2016: 4 · 2015: 3 · 2014: 6 · 2013: 8 · 2012: 8
FWCI
10.40
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Public Health Service
  • National Institute on Aging (P01AG010491, AG10491)
  • National Cancer Institute (CA 100123, R01CA100123)
  • National Institute of Neurological Disorders and Stroke (NS45913, R01NS045913, NS42017)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
Keywords
statins, Alzheimer's disease, amyloid precursor protein, alpha-secretase, ectodomain shedding, ROCK1, Rho kinase, Rho GTPases, isoprenoid pathway, farnesyltransferase inhibitors, atorvastatin, simvastatin, HMG-CoA reductase, neuroblastoma cells, protein phosphorylation
MeSH terms
Atorvastatin, Alzheimer Disease, Amino Acid Sequence, Heptanoic Acids, Humans, Molecular Sequence Data, Neuroblastoma, Phosphorylation, Pyrroles, Tumor Cells, Cultured, Amyloid beta-Protein Precursor, Protein Serine-Threonine Kinases, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Simvastatin, Intracellular Signaling Peptides and Proteins, rho-Associated Kinases

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