Skip to main content
SpringerLink
Log in

Inhibitors of Tau-Phosphorylating Kinases

  • Chapter
  • First Online:
Alzheimer’s Disease II

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 24))

Abstract

The phosphorylation of tau protein is finely regulated by a balance between phosphorylation and dephosphorylation processes carried out by kinases and phosphatases. It has been suggested that the disruption of this equilibrium and consequent abnormal tau phosphorylation contribute to the aggregation of tau. The understanding of this important mechanism is of high interest because of the implication of tau aggregates in the development of Alzheimer’s disease (AD). In the last few years, among the possible strategies which could be used to reduce tau phosphorylation, the inhibition of certain tyrosine kinases has been suggested as a promising alternative to the common therapeutic approaches. In this chapter we will first give an overview of the tau protein kinases, their roles in cells, regulation and importance in AD. This will be followed by a more detailed description of the role of Fyn, a member of the Src family kinases, in the physiological development of CNS and the pathological progress of AD. How the inhibition of Fyn could be used as a new strategy in the fight against AD will be discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

5-HT6R:

5-Hydroxytryptamine 6 receptor

AD:

Alzheimer’s disease

ADRA:

Alzheimer’s Disease and Related Disorders Association

AMPAR:

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor

APP:

Amyloid precursor protein

Aβ:

Amyloid β

Blk:

B lymphocyte kinase

CaMKII:

Ca2+/calmodulin-dependent protein kinase II

CDK5:

Cyclin-dependent protein kinase-5

CHK1:

Checkpoint kinase 1

CIs:

Cholinesterase inhibitors

CK:

Casein kinase

c-KitR:

c-Kit receptor

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

Csk:

C-terminal Src kinase

DYRK:

Dual-specificity tyrosine phosphorylation-regulated kinase

ECM:

Extracellular matrix

EGFR:

Epidermal growth factor receptor

Erk:

Signal-regulated kinase

FAD:

Familial Alzheimer’s disease

Fgr:

Gardner-Rasheed feline sarcoma viral (v-fgr) oncogene homolog

Frk:

Fyn-related kinase

GABA(A)R:

γ-Aminobutyric acid A receptor

GAP:

GTPase-activating protein

GSK3:

Glycogen synthase kinase-3

HRI:

Hydrophobic region I

HRII:

Hydrophobic region II

IGF-1R:

Insulin-like growth factor 1 receptor

JAK2:

Janus kinase 2

JNK:

c-Jun N-terminal kinase

KDR:

Kinase insert domain receptor

Lck:

Lymphocyte-specific tyrosine kinase

MAP:

Microtubule-associated protein

MAPK:

Mitogen-activated protein kinases

MARK:

Microtubule affinity-regulating kinases

MBD:

Microtubule-binding domain

MCI:

Mild cognitive impairment

MCT:

Mast cell tumours

MD:

Molecular dynamics

MMGBSA:

Molecular mechanics Generalised born surface area

mTOR:

Mammalian Target of Rapamycin

NFT:

Neurofibrillary tangles

NIA:

National Institute of Ageing

NINCDS:

National Institute of Neurological and Communicative Disorders and Stroke

NMDA:

N-methyl-d-aspartate

NMDAR:

NMDA receptor

Non-PDPK:

Non-proline-directed protein kinases

nRTK:

Non-receptor tyrosine kinase

NSAIDs:

Nonsteroidal anti-inflammatory drugs

PDGFR:

Platelet-derived growth factor receptor

PDPK:

Proline-directed protein kinases

PhK:

Phosphorylase kinase

PKA:

Protein kinase A

PKB:

Protein kinase B

PKC:

Protein kinase C

PKN:

Protein kinase N

PrP:

Cellular prion protein

PSD:

Postsynaptic density

PyrPyr:

Pyrazolo[3,4-d]pyrimidine

RPTP:

Receptor protein tyrosine phosphatase

SFK:

Src family kinase

SP:

Senile plaques

Syk:

Spleen tyrosine kinase

TK:

Tyrosine kinase

TPK:

Tyrosine protein kinases

TTBK:

Tau-tubulin kinase

WHO:

World Health Organization

References

  1. NIH National Institute of Aging. Alzheimer’s Disease Fact Sheet. NIH Publication No. 15-6423, May 2015. Available at https://www.nia.nih.gov/alzheimers/publication/alzheimers-disease-fact-sheet

  2. Berchtold NC, Cotman CW (1998) Evolution in the conceptualization of Dementia and Alzheimer’s disease: Greco-Roman period to the 1960s. Neurobiol Aging 19:173–189

    Article  CAS  Google Scholar 

  3. Stelzmann RA, Schnitzlein HN, Murtagh FR (1995) An English Translation of Alzheimer’s 1907 Paper, “Über eine eigenartige Erlranliung der Hirnrinde”. Clin Anat 8:429–431

    Article  Google Scholar 

  4. Kidd M (1963) Paired helical filaments in electron microscopy of Alzheimer’s disease. Nature 197:192–193

    Article  CAS  Google Scholar 

  5. Alzheimer’s Association (2016) http://www.alz.org/

  6. World Health Organization (2015) http://www.who.int/mediacentre/factsheets/fs404/en/

  7. Qui C (2009) Epidemiology of Alzheimer's disease: occurrence, determinants, and strategies toward intervention dialogues. Clin Neurosci 11:111–128

    Google Scholar 

  8. Alzheimer’s Association (2016) Alzheimer’s disease facts and figures. Alzheimers Dement 12:459–509

    Article  Google Scholar 

  9. Hebert LE, Weuve J, Scherr PA et al (2013) Alzheimer disease in the United States (2010–2050) estimated using the 2010 census. Neurology 80:1778–1783

    Article  Google Scholar 

  10. McKhann G, Drachman D, Folstein M et al (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS‐ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34:939–944

    Article  CAS  Google Scholar 

  11. Jack CR, Albert MS, Knopman DS et al (2011) Introduction to the recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 7:257–262

    Article  Google Scholar 

  12. McKhann GM, Knopman DS, Chertkow H et al (2011) The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7:263–269

    Article  Google Scholar 

  13. Albert MS, DeKosky ST, Dickson D et al (2011) The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7:270–279

    Article  Google Scholar 

  14. Sperling RA, Aisen PS, Becket LA et al (2011) Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7:280–292

    Article  Google Scholar 

  15. Reitz C, Mayeux R (2014) Alzheimer disease: epidemiology, diagnostic criteria, risk factors and biomarkers. Biochem Pharmacol 88:640–651

    Article  CAS  Google Scholar 

  16. Rosenberg RN (2000) The molecular and genetic basis of AD: the end of the beginning: the 2000 Wartenberg lecture. Neurology 54:2045–2054

    Article  CAS  Google Scholar 

  17. Crews L, Masliah E (2010) Molecular mechanisms of neurodegeneration in Alzheimer’s disease. Hum Mol Genet 19:R12–R20

    Article  CAS  Google Scholar 

  18. Terry RD, Masliah E, Salmon DP et al (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30:572–580

    Article  CAS  Google Scholar 

  19. DeKosky S, Scheff S (1990) Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann Neurol 27:457–464

    Article  CAS  Google Scholar 

  20. Monczor M (2005) Diagnosis and treatment of Alzheimer's disease. Curr Med Chem 5:5–13

    CAS  Google Scholar 

  21. Fountoulakis M, Kossida S (2006) Proteomics-driven progress in neurodegeneration research. Electrophoresis 27:1556–1573

    Article  CAS  Google Scholar 

  22. Akiyama H, Barger S, Barnum S et al (2000) Inflammation and Alzheimer’s disease. Neurobiol Aging 21:383–421

    Article  CAS  Google Scholar 

  23. Wyss-Coray T (2006) Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat Med 12:1005–1015

    CAS  Google Scholar 

  24. McGeer PL, Schulzer M, McGeer EG (1996) Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease: a review of 17 epidemiologic studies. Neurology 47:425–432

    Article  CAS  Google Scholar 

  25. Bartus RT, Dean RL, Beer B et al (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science 217:408–417

    Article  CAS  Google Scholar 

  26. Perry EK (1986) The cholinergic hypothesis-ten years on. Br Med Bull 42:63–69

    Article  CAS  Google Scholar 

  27. Contestabile A (2011) The history of the cholinergic hypothesis. Behav Brain Res 221:334–340

    Article  CAS  Google Scholar 

  28. Cacabelos R, Takeda M, Winbland B (1999) The glutamatergic system and neurodegeneration in dementia: preventive strategies in Alzheimer's disease. Int J Geriatr Psychiatry 14:3–47

    Article  CAS  Google Scholar 

  29. Selkoe DJ (1991) The molecular pathology of Alzheimer's disease. Neuron 6:487–498

    Article  CAS  Google Scholar 

  30. Hardy JA, Higgings GA (1992) Alzheimer's disease: the amyloid cascade hypothesis. Science 256:184–185

    Article  CAS  Google Scholar 

  31. Karran E, De Strooper B (2016) The amyloid cascade hypothesis: are we poised for success or failure? J Neurochem. doi:10.1111/jnc.13632 (published ahead of print, June 2016)

  32. Morishima-Kawashima M, Ihara Y (2002) Alzheimer's disease: β-amyloid protein and tau. Neurosci Res 70:392–401

    Article  CAS  Google Scholar 

  33. Querfurth HW, LaFerla FM (2010) Alzheimer's disease. N Engl J Med 362:329–344

    Article  CAS  Google Scholar 

  34. Johnson RD, Steel DG, Gafni A (2014) Structural evolution and membrane interactions of Alzheimer's amyloid-β peptide oligomers: new knowledge from single-molecule fluorescence studies. Protein Sci 23:869–883

    Article  CAS  Google Scholar 

  35. Iqbal K, Liu F, Gong CX et al (2010) Tau in Alzheimer disease and related tauopathies. Curr Alzheimer Res 7:656–664

    Article  CAS  Google Scholar 

  36. Gendron TF, Petrucelli L (2009) The role of tau in neurodegeneration. Mol Neurodegener 4:13

    Article  CAS  Google Scholar 

  37. Martin L, Latypova X, Wilson CM et al (2013) Tau protein kinases: involvement in Alzheimer’s disease. Ageing Res Rev 12:289–309

    Article  CAS  Google Scholar 

  38. Drewes G, Trinczek B, Illenberger S et al (1995) Microtubule-associated protein/microtubule affinity-regulating kinase (p110mark). A novel protein kinase that regulates tau-microtubule interactions and dynamic instability by phosphorylation at the Alzheimer-specific site serine 262. J Biol Chem 270:7679–7688

    Article  CAS  Google Scholar 

  39. Sengupta A, Kabat J, Novak M et al (1998) Phosphorylation of tau at both Thr231 and Ser262 is required for maximal inhibition of its binding to microtubules. Arch Biochem Biophys 357:299–309

    Article  CAS  Google Scholar 

  40. Sergeant N, Delacourte A, Buée L (2005) Tau protein as a differential biomarker of tauopathies. Biochim Biophys Acta 1739:179–197

    Article  CAS  Google Scholar 

  41. Yiannopoulou KG, Papageorgiou SG (2013) Current and future treatments for Alzheimer’s disease. Ther Adv Neurol Disord 6:19–33

    Article  CAS  Google Scholar 

  42. Cheng X, Zhang L, Lian YJ (2015) Molecular targets in Alzheimer’s disease: from pathogenesis to therapeutics. Biomed Res Int 2015:760758

    Google Scholar 

  43. Birks J, Harvey RJ (2006) Donepezil for dementia due to Alzheimer's disease. Cochrane Database Syst Rev 1, CD001190

    Google Scholar 

  44. Scott LJ, Goa KL (2000) Galantamine: a review of its use in Alzheimer's disease. Drugs 60:1095–1122

    Article  CAS  Google Scholar 

  45. Reisberg B, Doody R, Stöffler A et al (2003) Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med 348:1333–1341

    Article  CAS  Google Scholar 

  46. Winblad B, Grossberg G, Frölich L et al (2007) A 6-month, double-blind, placebo-controlled study of the first skin patch for Alzheimer disease. Neurology 69:S14–S22

    Article  CAS  Google Scholar 

  47. Atri A, Hendrix SB, Pejović V et al (2015) Cumulative, additive benefits of memantine-donepezil combination over component monotherapies in moderate to severe Alzheimer's dementia: a pooled area under the curve analysis. Alzheimers Res Ther 7:28

    Article  CAS  Google Scholar 

  48. Hansen RA, Gartlehner G, Webb AP et al (2008) Efficacy and safety of donepezil, galantamine, and rivastigmine for the treatment of Alzheimer’s disease: a systematic review and meta-analysis. Clin Interv Aging 3:211–225

    CAS  Google Scholar 

  49. Maidment ID, Fox CG, Boustani M et al (2008) Efficacy of memantine on behavioural and psychological symptoms related to dementia: a systematic meta-analysis. Ann Pharmacother 42:32–38

    Article  Google Scholar 

  50. Lee G, Neve RL, Kosik KS (1989) The microtubule binding domain of tau protein. Neuron 2:1615–1624

    Article  CAS  Google Scholar 

  51. LaPointe NE, Morfini G, Pigino G et al (2009) The amino terminus of tau inhibits kinesin-dependent axonal transport: implications for filament toxicity. J Neurosci Res 87:440–451

    Article  CAS  Google Scholar 

  52. Arriagada PV, Growdon JH, Hedley-Whyte ET et al (1992) Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease. Neurology 42:631–639

    Article  CAS  Google Scholar 

  53. Embi N, Rylatt DB, Cohen P (1980) Glycogen synthase kinase-3 from rabbit skeletal muscle. Separation from cyclic-AMP-dependent protein kinase and phosphorylase kinase. Eur J Biochem 107:519–527

    Article  CAS  Google Scholar 

  54. Eldar-Finkelman H, Martinez A (2011) GSK-3 inhibitors: preclinical and clinical focus on CNS. Front Mol Neurosci 4:32

    Article  CAS  Google Scholar 

  55. Hooper C, Killick R, Lovestone S (2008) The GSK3 hypothesis of Alzheimer’s disease. J Neurochem 104:1433–1439

    Article  CAS  Google Scholar 

  56. Rayasam GV, Tulasi VK, Sodhi R et al (2009) Glycogen synthase kinase 3: more than a name sake. Br J Pharmacol 156:885–898

    Article  CAS  Google Scholar 

  57. Beurel E, Michalek SM, Jope RS (2010) Innate and adaptive immune responses regulated by glycogen synthase kinase-3 (GSK3). Trends Immunol 31:24–31

    Article  CAS  Google Scholar 

  58. Woodgett JR (1990) Molecular cloning and expression of glycogen synthase kinase-3/factor A. EMBO J 9:2431–2438

    Google Scholar 

  59. Mukai F, Ishiguro K, Sano Y et al (2002) Alternative splicing isoform of tau protein kinase 1/glycogen synthase kinase 3beta. J Neurochem 81:1073–1083

    Article  CAS  Google Scholar 

  60. Hanger DP, Anderton BH, Noble W (2009) Tau phosphorylation: the therapeutic challenge for neurodegenerative disease. Trends Mol Med 15:112–119

    Article  CAS  Google Scholar 

  61. Lucas JJ, Hernández F, Gómez-Ramos P et al (2001) Decreased nuclear beta-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3beta conditional transgenic mice. EMBO J 20:27–39

    Article  CAS  Google Scholar 

  62. Hoshi M, Takashima A, Noguchi K et al (1996) Regulation of mitochondrial pyruvate dehydrogenase activity by tau protein kinase I/glycogen synthase kinase 3beta in brain. Proc Natl Acad Sci U S A 93:2719–2723

    Article  CAS  Google Scholar 

  63. Gómez de Barreda E, Pérez M, Gómez Ramos P et al (2010) Tau-knockout mice show reduced GSK3-induced hippocampal degeneration and learning deficits. Neurobiol Dis 37:622–629

    Article  CAS  Google Scholar 

  64. Yamaguchi H, Ishiguro K, Uchida T et al (1996) Preferential labelling of Alzheimer neurofibrillary tangles with antisera for tau protein kinase (TPK) I/glycogen synthase kinase-3 beta and cyclin-dependent kinase 5, a component of TPK II. Acta Neuropathol 92:232–241

    Article  CAS  Google Scholar 

  65. Pei JJ, Tanaka T, Tung YC et al (1997) Distribution, levels, and activity of glycogen synthase kinase-3 in the Alzheimer disease brain. J Neuropathol 56:70–78

    Article  CAS  Google Scholar 

  66. Leroy K, Yilmaz Z, Brion JP (2007) Increased level of active GSK-3beta in Alzheimer’s disease and accumulation in argyrophilic grains and in neurons at different stages of neurofibrillary degeneration. Neuropathol Appl Neurobiol 33:43–55

    Article  CAS  Google Scholar 

  67. Smith D (2003) Cdk5 in neuroskeletal dynamics. Neurosignals 12:239–251

    Article  CAS  Google Scholar 

  68. Nikolic M, Dudek H, Kwon YT et al (1996) The cdk5/p35 kinase is essential for neurite outgrowth during neuronal differentiation. Genes Dev 10:816–825

    Article  CAS  Google Scholar 

  69. Barclay JW, Aldea M, Craig TJ et al (2007) Regulation of the fusion pore conductance during exocytosis by cyclin-dependent kinase 5. J Biol Chem 279:41495–41503

    Article  CAS  Google Scholar 

  70. Samuels BA, Hsueh YP, Shu T et al (2007) Cdk5 promotes synaptogenesis by regulating the subcellular distribution of the MAGUK family member CASK. Neuron 56:823–837

    Article  CAS  Google Scholar 

  71. Humbert S, Dhavan R, Tsai L (2000) p39 activates cdk5 in neurons, and is associated with the actin cytoskeleton. J Cell Sci 113:975–983

    CAS  Google Scholar 

  72. Dhariwala FA, Rajadhyaksha MS (2008) An unusual member of the Cdk family: Cdk5. Cell Mol Neurobiol 28:351–369

    Article  CAS  Google Scholar 

  73. Patrick GN, Zukerberg L, Nikolic M et al (1999) Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 402:615–622

    Article  CAS  Google Scholar 

  74. Noble W, Olm V, Takata K et al (2003) Cdk5 is a key factor in tau aggregation and tangle formation in vivo. Neuron 38:555–565

    Article  CAS  Google Scholar 

  75. Sengupta A, Wu Q, Grundke-Iqbal I et al (1997) Potentiation of GSK-3-catalyzed Alzheimer-like phosphorylation of human tau by cdk5. Mol Cell Biochem 167:99–105

    Article  CAS  Google Scholar 

  76. Cheung ZH, Gong K, Ip NY (2008) Cyclin-dependent kinase 5 supports neuronal survival through phosphorylation of Bcl-2. J Neurosci 28:4872–4877

    Article  CAS  Google Scholar 

  77. Lopes JP, Oliveira CR, Agostinho P (2010) Neurodegeneration in Aβ-induced model of Alzheimer’s disease: the role of Cdk5. Aging Cell 9:64–77

    Article  CAS  Google Scholar 

  78. Atzori C, Ghetti B, Piva R et al (2001) Activation of the JNK/p38 pathway occurs in diseases characterized by tau protein pathology and is related to tau phosphorylation but not apoptosis. J Neuropathol Exp Neurol 60:1190–1197

    Article  CAS  Google Scholar 

  79. Ferrer I, Blanco R, Carmona M et al (2001) Phosphorylated map kinase (ERK1, ERK2) expression is associated with early tau deposition in neurones and glial cells, but not with increased nuclear DNA vulnerability and cell death, in Alzheimer disease. Brain Pathol 11:144–158

    Article  CAS  Google Scholar 

  80. Remy G, Risco AM, Iñesta-Vaquera FA et al (2010) Differential activation of p38MAPK isoforms by MKK6 and MKK3. Cell Signal 22:660–667

    Article  CAS  Google Scholar 

  81. Sergeant N, Bretteville A, Hamdane M et al (2008) Biochemistry of tau in Alzheimer’s disease and related neurological disorders. Expert Rev Proteomics 5:207–224

    Article  CAS  Google Scholar 

  82. Thornton TM, Pedraza-Alva G, Deng B et al (2008) Phosphorylation by p38 MAPK as an alternative pathway for GSK3beta inactivation. Science 320:667–670

    Article  CAS  Google Scholar 

  83. Yang Y, Zhu X, Chen Y et al (2007) p38 and JNK MAPK, but not ERK1/2 MAPK, play an important role in cholchicine-induced cortical neurons apoptosis. Eur J Pharmacol 576:26–33

    Article  CAS  Google Scholar 

  84. Cuadrado A, Nebreda AR (2010) Mechanisms and functions of p38 MAPK signalling. Biochem J 429:403–417

    Article  CAS  Google Scholar 

  85. Zhu X, Rottkamp CA, Boux H et al (2000) Activation of p38 links tau phosphorylation, oxidative stress, and cell cycle-related events in Alzheimer disease. J Neuropathol Exp Neurol 59:880–888

    Article  CAS  Google Scholar 

  86. Munoz L, Ammit AJ (2010) Targeting p38 MAPK pathway for the treatment of Alzheimer’s disease. Neuropharmacology 58:561–568

    Article  CAS  Google Scholar 

  87. Guise S, Braguer D, Carles G et al (2001) Hyperphosphorylation of tau is mediated by ERK activation during anticancer drug-induced apoptosis in neuroblastoma cells. J Neurosci Res 63:257–267

    Article  CAS  Google Scholar 

  88. Medina MG, Ledesma MD, Domínguez JE et al (2005) Tissue plasminogen activator mediates amyloid-induced neurotoxicity via Erk1/2 activation. EMBO J 24:1706–1716

    Article  CAS  Google Scholar 

  89. Pei JJ, Braak H, An WL et al (2002) Up-regulation of mitogen-activated protein kinase ERK1/2 and MEK1/2 is associated with the progression of neurofibrillary degeneration in Alzheimer’s disease. Brain Res Mol Brain Res 109:45–55

    Article  CAS  Google Scholar 

  90. Wada T, Penninger JM (2004) Mitogen-activated protein kinases in apoptosis regulation. Oncogene 23:2838–2849

    Article  CAS  Google Scholar 

  91. Zhu X, Raina AK, Rottkamp CA et al (2001) Activation and redistribution of c-jun-N-terminal kinase/stress activated protein kinase in degenerating neurons in Alzheimer’s disease. J Neurochem 76:435–441

    Article  CAS  Google Scholar 

  92. Shen C, Chen Y, Liu H et al (2008) Hydrogen peroxide promotes Abeta production through JNK-dependent activation of gamma-secretase. J Biol Chem 283:17721–17730

    Article  CAS  Google Scholar 

  93. Houlden H, Johnson J, Gardner-Thorpe C et al (2007) Mutations in TTBK2, encoding a kinase implicated in tau phosphorylation, segregate with spinocerebellar ataxia type 11. Nat Genet 39:1434–1436

    Article  CAS  Google Scholar 

  94. Sato S, Xu J, Okuyama S et al (2008) Spatial learning impairment, enhanced CD5/p35 activity, and downregulation of NMDA receptor expression in transgenic tau-tubulin kinase 1. J Neurosci 28:14511–14521

    Article  CAS  Google Scholar 

  95. Li G, Yin H, Kuret J (2004) Casein kinase 1 delta phosphorylates tau and disrupts its binding to microtubules. J Biol Chem 279:15938–15945

    Article  CAS  Google Scholar 

  96. Hanger DP, Byers HL, Wray S et al (2007) Novel phosphorylation sites in tau from Alzheimer brain support a role for casein kinase 1 in disease pathogenesis. J Biol Chem 282:23645–23654

    Article  CAS  Google Scholar 

  97. Liu C, Li Y, Semenov M et al (2002) Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell 108:837–847

    Article  CAS  Google Scholar 

  98. Ahmad KA, Wang G, Unger G et al (2008) Protein kinase CK2-a key suppressor of apoptosis. Adv Enzyme Regul 48:179–187

    Article  CAS  Google Scholar 

  99. Knippschild U, Gocht A, Wolff S et al (2005) The casein kinase I family: participation in multiple cellular processes in eukaryotes. Cell Signal 17:675–689

    Article  CAS  Google Scholar 

  100. Chauhan A, Chauhan VP, Murakami N (1993) Amyloid beta-protein stimulates casein kinase I and casein kinases II activities. Brain Res 629:47–52

    Article  CAS  Google Scholar 

  101. Schwab C, DeMaggio AJ, Ghoshal N et al (2000) Casein kinase I delta is associated with pathological accumulation of tau in several neurodegenerative diseases. Neurobiol Aging 21:503–510

    Article  CAS  Google Scholar 

  102. Yasojima K, Kuret J, DeMaggio AJ et al (2000) Casein kinase 1 delta mRNA is upregulated in Alzheimer disease brain. Brain Res 865:116–120

    Article  CAS  Google Scholar 

  103. Ferrer I, Barrachina M, Puig B et al (2005) Constitutive Dyrk1A is abnormally expressed in Alzheimer disease, Down syndrome, Pick disease, and related transgenic models. Neurobiol Dis 20:392–400

    Article  CAS  Google Scholar 

  104. Yang EJ, Ahn YS, Chung KC (2001) Protein kinase Dyrk1 activates cAMP response element-binding protein during neuronal differentiation in hippocampal progenitor cells. J Biol Chem 276:39819–39824

    Article  CAS  Google Scholar 

  105. Chen H, Antonarakis SE (1997) Localisation of a human homologue of the Drosophila mnb and rat Dyrk genes to chromosome 21q22.2. Hum Genet 99:262–265

    Article  CAS  Google Scholar 

  106. Masters CL, Simms G, Weinman NA et al (1985) Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A 82:4245–4249

    Article  CAS  Google Scholar 

  107. Kimura R, Kamino K, Yamamoto M et al (2007) The DYRK1A gene, encoded by chromosome 21 Down syndrome critical region, bridges between beta-amyloid production and tau phosphorylation in Alzheimer disease. Hum Mol Genet 16:15–23

    Article  CAS  Google Scholar 

  108. Dell'Acqua ML, Scott JD (1997) Protein kinase A anchoring. J Biol Chem 272:12881–12884

    Article  Google Scholar 

  109. Tian Q, Zhang JX, Zhang Y et al (2009) Biphasic effects of forskolin on tau phosphorylation and spatial memory in rats. J Alzheimers Dis 17:631–642

    Article  CAS  Google Scholar 

  110. Soderling TR (1999) The Ca-calmodulin-dependent protein kinase cascade. Trends Biochem Sci 24:232–236

    Article  CAS  Google Scholar 

  111. Xie S, Jin N, Gu J et al (2016) O-GlcNAcylation of protein kinase A catalytic subunits enhances its activity: a mechanism linked to learning and memory deficits in Alzheimer's disease. Aging Cell 15:455–464

    Article  CAS  Google Scholar 

  112. Kitagawa M, Mukai H, Shibata H et al (1995) Purification and characterization of a fatty acid-activated protein kinase (PKN) from rat testis. Biochem J 310:657–664

    Article  CAS  Google Scholar 

  113. Taniguchi T, Kawamata T, Mukai H et al (2001) Phosphorylation of tau is regulated by PKN. J Biol Chem 276:10025–10031

    Article  CAS  Google Scholar 

  114. Isagawa T, Mukai H, Oishi K et al (2000) Dual effects of PKNalpha and protein kinase C on phosphorylation of tau protein by glycogen synthase kinase-3beta. Biochem Biophys Res Commun 273:209–212

    Article  CAS  Google Scholar 

  115. Grifith LC (2004) Regulation of calcium/calmodulin-dependent protein kinase II activation by intramolecular and intermolecular interactions. J Neurosci 24:8394–8398

    Article  CAS  Google Scholar 

  116. Yamamoto H, Hiragami Y, Murayama M et al (2005) Phosphorylation of tau at serine 416 by Ca2+/calmodulin-dependent protein kinase II in neuronal soma in brain. J Neurochem 94:1438–1447

    Article  CAS  Google Scholar 

  117. Wang YJ, Chen GH, Hu XY et al (2005) The expression of calcium/calmodulin-dependent protein kinase II-alpha in the hippocampus of patients with Alzheimer’s disease and its links with AD-related pathology. Brain Res 1031:101–108

    Article  CAS  Google Scholar 

  118. Tsukane M, Yamauchi T (2009) Ca2+/calmodulin-dependent protein kinase II mediates apoptosis of P19 cells expressing human tau during neural differentiation with retinoic acid treatment. J Enzyme Inhib Med Chem 24:365–371

    Article  CAS  Google Scholar 

  119. Lee G, Thangavel R, Sharma VM et al (2004) Phosphorylation of tau by fyn: implications for Alzheimer’s disease. J Neurosci 24:2304–2312

    Article  CAS  Google Scholar 

  120. Derkinderen P, Scales TM, Hanger DP et al (2005) Tyrosine 394 is phosphorylated in Alzheimer’s paired helical filament tau and in fetal tau with c-Abl as the candidate tyrosine kinase. J Neurosci 25:6584–6593

    Article  CAS  Google Scholar 

  121. Vega IE, Cui L, Propst JA et al (2005) Increase in tau tyrosine phosphorylation correlates with the formation of tau aggregates. Brain Res 138:135–144

    Article  CAS  Google Scholar 

  122. Lebouvier T, Scales TM, Williamson R et al (2009) The microtubule-associated tau is also phosphorylated on tyrosine. J Alzheimers Dis 18:1–9

    Article  CAS  Google Scholar 

  123. Van Etten RA (1999) Cycling, stressed-out and nervous: cellular functions of c-Abl. Trends Cell Biol 9:179–186

    Article  Google Scholar 

  124. Plattner R, Kadlec L, DeMali KA et al (1999) c-Abl is activated by growth factors and Src family kinases and has a role in the cellular response to PDGF. Genes Dev 13:2400–2411

    Article  CAS  Google Scholar 

  125. Vázquez MC, Vargas LM, Inestrosa NC et al (2009) c-Abl modulates AICD dependent cellular responses: transcriptional induction and apoptosis. J Cell Physiol 220:136–143

    Article  CAS  Google Scholar 

  126. Tell V, Hilgeroth A (2013) Recent developments of protein kinase inhibitors as potential AD therapeutics. Front Cell Neurosci 7:189

    Article  CAS  Google Scholar 

  127. Godyń J, Jończyk J, Panek D et al (2016) Therapeutic strategies for Alzheimer's disease in clinical trials. Pharmacol Rep 68:127–138

    Article  CAS  Google Scholar 

  128. Silva T, Reis J, Teixera J et al (2014) Alzheimer’s disease, enzyme targets and drug discovery struggles: from natural products to drug prototypes. Ageing Res Rev 15:116–145

    Article  CAS  Google Scholar 

  129. Kumar A, Singh A, Ekavali (2015) A review on Alzheimer’s disease pathophysiology and its management: an update. Pharmacol Rep 67:195–203

    Article  CAS  Google Scholar 

  130. Ellis L (2016) Alzheimer’s disease: defusing the bomb by 2015. IN VIVO: The Business & Medicine Report 34:30–37

    Google Scholar 

  131. Geldenhuys WJ, Darvesh AS (2015) Pharmacotherapy of Alzheimer’s disease: current and future trends. Expert Rev Neurother 15:3–5

    Article  CAS  Google Scholar 

  132. Mairet-Coello G, Polleux F (2014) Involvement of ‘stress–response’ kinase pathways in Alzheimer’s disease progression. Curr Opin Neurobiol 27:110–117

    Article  CAS  Google Scholar 

  133. Krug M, Hilgeroth A (2008) Recent advances in the development of multi-kinase inhibitors. Mini Rev Med Chem 8:1312–1327

    Article  CAS  Google Scholar 

  134. Zhang J, Yang PL, Gray NS (2009) Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer 9:28–29

    Article  CAS  Google Scholar 

  135. Nygaard HB, van Dyck CH, Strittmatter SM (2014) Fyn kinase inhibition as a novel therapy for Alzheimer’s disease. Alzheimers Res Ther 6:8

    Article  Google Scholar 

  136. Summy JM, Gallick GE (2003) Src family kinases in tumor progression and metastasis. Cancer Metastasis Rev 22:337–358

    Article  CAS  Google Scholar 

  137. Guarino M (2010) Src signaling in cancer invasion. J Cell Physiol 223:14–26

    CAS  Google Scholar 

  138. Summy JM, Gallick GE (2003) Treatment for advanced tumors: SRC reclaims center stage. Clin Cancer Res 12:1398–1401

    Article  Google Scholar 

  139. Goel RK, Lukong KE (2016) Understanding the cellular roles of Fyn-related kinase (FRK): implications in cancer biology. Cancer Metastasis Rev 35:179–199

    Article  CAS  Google Scholar 

  140. Thomas SM, Brugge JS (1997) Cellular functions regulated by Src family kinases. Annu Rev Cell Dev Biol 13:513–609

    Article  CAS  Google Scholar 

  141. Goldsmith JF, Hall CG, Atkinson TP (2002) Identification of an alternatively spliced isoform of the fyn tyrosine kinase. Biochem Biophys Res Commun 298:501–504

    Article  CAS  Google Scholar 

  142. Knighton DR, Zheng JH, Ten Eyck LF et al (1991) Crystal structure of the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase. Science 253:407–414

    Article  CAS  Google Scholar 

  143. Songyang Z, Steven ES, Manas C et al (1993) SH2 domains recognize specific phosphopeptide sequences. Cell 72:767–778

    Article  CAS  Google Scholar 

  144. Songyang Z, Shoelson SE, McGlade J et al (1994) Specific motifs recognized by the SH2 domains of Csk, 3BP2, fps/fes, GRB-2, HCP, SHC, Syk, and Vav. Mol Cell Biol 14:2777–2785

    Article  CAS  Google Scholar 

  145. Cohen GB, Ren R, Baltimore D (1995) Modular binding domains in signal transduction proteins. Cell 80:237–248

    Article  CAS  Google Scholar 

  146. Ren R, Mayer BJ, Cicchetti P et al (1993) Identification of a ten-amino acid proline-rich SH3 binding site. Science 259:1157–1161

    Article  CAS  Google Scholar 

  147. Mayer BJ, Eck MJ (1995) SH3 domains. Minding your p's and q's. Curr Biol 5:364–367

    Article  CAS  Google Scholar 

  148. zur Hausen JD, Burn P, Amrein KE (1997) Co-localization of Fyn with CD3 complex, CD45 or CD28 depends on different mechanisms. Eur J Immunol 27:2643–2649

    Google Scholar 

  149. Sigal CT, Zhou W, Buser CA et al (1994) Amino-terminal basic residues of Src mediate membrane binding through electrostatic interaction with acidic phospholipids. Proc Natl Acad Sci U S A 91:12253–12257

    Article  CAS  Google Scholar 

  150. Alland L, Peseckis SM, Atherton RE et al (1994) Dual myristoylation and palmitoylation of Src family member p59fyn affects subcellular localization. J Biol Chem 269:16701–16705

    CAS  Google Scholar 

  151. Salmond RJ, Filby A, Qureshi I et al (2009) T-cell receptor proximal signaling via the Src-family kinases, Lck and Fyn, influences T-cell activation, differentiation and tolerance. Immunol Rev 228:9–22

    Article  CAS  Google Scholar 

  152. Grant SG, O’Dell TJ, Karl KA et al (1992) Impaired long-term potentiation, spatial learning and hippocampal development in fyn mutant mice. Science 258:1903–1910

    Article  CAS  Google Scholar 

  153. Osterhout DJ, Wolven A, Wolven A, Wolf RM et al (1999) Morphological differentiation of oligodendrocytes requires activation of Fyn tyrosine kinase. J Cell Biol 145:1209–1218

    Article  CAS  Google Scholar 

  154. Macurek L, Dráberová L, Marková V et al (2008) Regulation of microtubule nucleation from membranes by complexes of membrane-bound gamma-tubulin with Fyn kinase and phosphoinositide 3-kinase. Biochem J 416:421–430

    Article  CAS  Google Scholar 

  155. Tezuka T, Umemori H, Akiyama T et al (1999) PSD-95 promotes Fyn-mediates Tyrosine phosphorylation of the N-methyl-d-aspartate receptor subunit NR2A. Proc Natl Acad Sci U S A 96:435–440

    Article  CAS  Google Scholar 

  156. Kalia LV, Salter MW (2003) Interactions between Src family protein tyrosine kinases and PSD-95. Neuropharmacol 45:720–728

    Google Scholar 

  157. Salter MW, Kalia LV (2004) Src kinases: a hub for NMDA receptor regulation. Nat Rev Neurosci 5:317–328

    Article  CAS  Google Scholar 

  158. Nada S, Shima T, Yanai H et al (2003) Identification of PSD-93 as a substrate for the Src family tyrosine kinase Fyn. J Biol Chem 278:47610–47621

    Article  CAS  Google Scholar 

  159. Jurd R, Tretter V, Walker J et al (2010) Fyn Kinase contributes to tyrosine phosphorylation of the GABA(A) receptor gamma2 subunit. Mol Cell Neurosci 44:129–134

    Article  CAS  Google Scholar 

  160. Taniguchi S, Liu H, Nakazawa T et al (2003) p250GAP, A neural RhoGAP protein is associated with and phosphorylated by Fyn. Biochem Biophys Res Commun 306:151–155

    Article  CAS  Google Scholar 

  161. Liang X, Draghi NA, Resh MD (2004) Signaling from integrins to Fyn to Rho family GTPase regulates morphologic differentiation of oligodendrocytes. J Neurosci 24:7140–7149

    Article  CAS  Google Scholar 

  162. Lim SH, Kwon SK, Lee MK et al (2009) Synapse formation regulated by protein tyrosine phosphatase receptor T through interaction with cell adhesion molecules and Fyn. EMBO J 28:3564–3578

    Article  CAS  Google Scholar 

  163. Wang PS, Wang J, Xiao ZC et al (2009) Protein-tyrosine phosphatase alpha acts as an upstream regulator of Fyn signaling to promote oligodendrocyte differentiation and myelination. J Biol Chem 284:33692–33702

    Article  CAS  Google Scholar 

  164. LaFerla FM, Green KN, Oddo S (2007) Intracellular amyloid-beta in Alzheimer's disease. Nat Rev Neurosci 8:499–509

    Article  CAS  Google Scholar 

  165. Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide. Nat Rev Mol Cell Biol 8:101–112

    Article  CAS  Google Scholar 

  166. Ballatore C, Lee VM, Trojanowski JQ (2007) Tau-mediated neurodegeneration in Alzheimer's disease and related disorders. Nat Rev Neurosci 8:663–672

    Article  CAS  Google Scholar 

  167. Wang JZ, Liu F (2008) Microtubule-associated protein tau in development, degeneration and protection of neurons. Prog Neurobiol 85:148–175

    Article  CAS  Google Scholar 

  168. Shirazi SK, Wood JG (1993) The protein tyrosine kinase, fyn, in Alzheimer's disease pathology. Neuroreport 4:435–437

    Article  CAS  Google Scholar 

  169. Luo YQ, Hirashima N, Li YH et al (1995) Physiological levels of beta-amyloid increase tyrosine phosphorylation and cytosolic calcium. Brain Res 681:65–74

    Article  CAS  Google Scholar 

  170. Klein WL, Krafft GA, Finch CE (2001) Targeting small Aβ oligomers: the solution to an Alzheimer’s disease conundrum? Trends Neurosci 24:219–224

    Article  CAS  Google Scholar 

  171. Chen S, Yadav SP, Surewicz WK (2010) Interaction between human prion protein and amyloid-beta (Aβ) oligomers: role of N-terminal residues. J Biol Chem 285:26377–26383

    Article  CAS  Google Scholar 

  172. Calella AM, Farinelli M, Nuvolone M et al (2010) Prion protein and Aβ-related synaptic toxicity impairment. EMBO Mol Med 2:306–314

    Article  CAS  Google Scholar 

  173. Balducci C, Beeg M, Stravalaci M et al (2010) Synthetic amyloid-beta oligomers impair long-term memory independently of cellular prion protein. Proc Natl Acad Sci U S A 107:2295–2300

    Article  CAS  Google Scholar 

  174. Lauren J, Gimbel DA, Nygaard HB et al (2009) Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature 457:1128–1132

    Article  CAS  Google Scholar 

  175. Um JW, Nygaard HB, Heiss JK et al (2012) Alzheimer amyloid-beta oligomer bound to postsynaptic prion protein activates Fyn to impair neurons. Nat Neurosci 15:1227–1235

    Article  CAS  Google Scholar 

  176. Um JW, Kaufman AC, Kostylev M et al (2013) Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer Aβ oligomer bound to cellular prion protein. Neuron 79:887–902

    Article  CAS  Google Scholar 

  177. Roberson ED, Scearce-Levie K, Palop JJ et al (2007) Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer’s disease mouse model. Science 316:750–754

    Article  CAS  Google Scholar 

  178. Bhaskar K, Hobbs GA, Yen SH et al (2010) Tyrosine phosphorylation of tau accompanies disease progression in transgenic mouse models of tauopathy. Neuropathol Appl Neurobiol 36:462–477

    Article  CAS  Google Scholar 

  179. Bhaskar K, Yen SH, Lee G (2005) Disease-related modifications in tau affect the interaction between Fyn and Tau. J Biol Chem 280:35119–35125

    Article  CAS  Google Scholar 

  180. Lee G, Newman ST, Gard DL et al (1998) Tau interacts with src-family non-receptor tyrosine kinases. J Cell Sci 111:3167–3177

    CAS  Google Scholar 

  181. Larson M, Sherman MA, Amar F et al (2012) The complex PrP(c)–Fyn couples human oligomeric Aβ with pathological tau changes in Alzheimer’s disease. J Neurosci 32:16857a-16871

    Google Scholar 

  182. Aarts M, Liu Y, Liu L et al (2002) Treatment of ischemic brain damage by perturbing NMDA receptor-PSD95 protein interactions. Science 298:846–850

    Article  CAS  Google Scholar 

  183. Ittner LM, Ke YD, Delerue F et al (2010) Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer’s disease mouse models. Cell 298:846–850

    Google Scholar 

  184. Yun HM, Kim S, Kim HJ et al (2007) The novel cellular mechanism of human 5-HT6 receptor through an interaction with Fyn. J Biol Chem 282:5496–5505

    Article  CAS  Google Scholar 

  185. Dubreuil P, Letard S, Ciufolini M (2009) Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT. PLoS One 4, e7258

    Article  CAS  Google Scholar 

  186. Marech I, Patruno R, Zizzo N et al (2014) Masitinib (AB1010), from canine tumor model to human clinical development: where we are? Crit Rev Oncol Hematol 91:98–111

    Article  Google Scholar 

  187. Demetri GD (2011) Differential properties of current tyrosine kinase inhibitors in gastrointestinal stromal tumors. Semin Oncol 38:S10–S19

    Article  CAS  Google Scholar 

  188. Mitry E, Hammel P, Deplanque G et al (2010) Safety and activity of masitinib in combination with gemcitabine in patients with advanced pancreatic cancer. Cancer Chemother Pharmacol 66:394–403

    Article  CAS  Google Scholar 

  189. Niederhoffer N, Levy R, Sick E et al (2009) Amyloid beta peptides trigger CD47-dependent mast cell secretory and phagocytic responses. Int J Immunopathol Pharmacol 22:473–483

    Article  CAS  Google Scholar 

  190. Maslinska D, Laure-Kamionowska M, Maslinski KT et al (2007) Distribution of tryptase-containing mast cells and metallothionein reactive astrocytes in human brains with amyloid deposits. Inflamm Res 5:S17–S18

    Article  CAS  Google Scholar 

  191. Piette F, Belmin J, Vincent H et al (2011) Masitinib as an adjunct therapy for mild-to-moderate Alzheimer's disease: a randomised, placebo-controlled phase 2 trial. Alzheimers Res Ther 3:16

    Article  CAS  Google Scholar 

  192. Hennequin LF, Allen J, Breed J et al (2006) N-(5-chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine, a novel, highly selective, orally available, dual-specific c-Src/Abl kinase inhibitor. J Med Chem 49:6465–6488

    Article  CAS  Google Scholar 

  193. Gangadhar TC, Clark JI, Karrison T et al (2013) Phase II study of the Src kinase inhibitor saracatinib (AZD0530) in metastatic melanoma. Invest New Drugs 31:769–773

    Article  CAS  Google Scholar 

  194. Gucalp A, Sparano JA, Caravelli J et al (2011) Phase II trial of saracatinib (AZD0530), an oral SRC-inhibitor for the treatment of patients with hormone receptor-negative metastatic breast cancer. Clin Breast Cancer 11:306–311

    Article  CAS  Google Scholar 

  195. Mackay HJ, Au HJ, McWhirter E et al (2012) A phase II trial of the Src kinase inhibitor saracatinib (AZD0530) in patients with metastatic or locally advanced gastric or gastro esophageal junction (GEJ) adenocarcinoma: a trial of the PMH phase II consortium. Invest New Drugs 30:1158–1163

    Article  CAS  Google Scholar 

  196. Fury MG, Baxi S, Shen R et al (2011) Phase II study of saracatinib (AZD0530) for patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Anticancer Res 31:249–253

    CAS  Google Scholar 

  197. Renouf DJ, Moore MJ, Hedley D et al (2012) A phase I/II study of the Src inhibitor saracatinib (AZD0530) in combination with gemcitabine in advanced pancreatic cancer. Invest New Drugs 30:779–786

    Article  CAS  Google Scholar 

  198. Hanke JH, Gardner JP, Dow RL et al (1996) Discovery of a novel, potent and Src family-selective tyrosine kinase inhibitor. Study of Lck- and Fyn T- dependent T cell activation. J Biol Chem 271:695–701

    Article  CAS  Google Scholar 

  199. Schenone S, Zanoli S, Crullo C et al (2008) Current advances in the development of anticancer drugs targeting tyrosine kinases of the Src family. Curr Drug Ther 3:158–176

    Article  CAS  Google Scholar 

  200. Tintori C, La Sala G, Vignaroli G et al (2015) Studies on the ATP binding site of Fyn kinase for the identification of new inhibitors and their evaluation as potential agents against tauopathies and tumors. J Med Chem 58:4590–4609

    Article  CAS  Google Scholar 

  201. Ryan DA, Narrow WC, Federoff HJ et al (2010) An improved method for generating consistent soluble amyloid-beta oligomer preparations for in vitro neurotoxicity studies. J Neurosci Methods 190:171–179

    Article  CAS  Google Scholar 

  202. Wong J, Higgins M, Halliday G et al (2012) Amyloid beta selectively modulates neuronal TrkB alternative transcript expression with implications for Alzheimer's disease. Neuroscience 210:363–374

    Article  CAS  Google Scholar 

  203. Kinoshita T, Matsubara M, Ishiguro H et al (2006) Structure of human Fyn kinase domain complexed with staurosporine. Biochem Biophys Res Commun 346:840–844

    Article  CAS  Google Scholar 

  204. Falchi F, Manetti F, Carraro F et al (2009) 3D QSAR models built on structure-based alignments of Abl tyrosine kinase inhibitors. ChemMedChem 6:976–987

    Article  CAS  Google Scholar 

  205. Kruewel T, Schenone S, Radi M et al (2010) Molecular characterization of c-Abl/c-Src kinase inhibitors targeted against murine tumour progenitor cells that express stem cell markers. PLoS One 5, e14143

    Article  CAS  Google Scholar 

  206. Radi M, Dreassi E, Brullo C et al (2011) Design, synthesis, biological activity, and ADME properties of pyrazolo[3,4-d]pyrimidines active in hypoxic human leukemia cells: a lead optimization study. J Med Chem 54:2610–2626

    Article  CAS  Google Scholar 

  207. Schenone S, Bruno O, Bondavalli F et al (2004) Antiproliferative activity of new 1-aryl-4-amino-1H-pyrazolo[3,4-d]pyrimidine derivatives toward the human epidermoid carcinoma A431 cell line. Eur J Med Chem 39:939–946

    Article  CAS  Google Scholar 

  208. Radi M, Brullo C, Crespan E et al (2011) Identification of potent c-Src inhibitors strongly affecting the proliferation of human neuroblastoma cells. Bioorg Med Chem Lett 21:5928–5933

    Article  CAS  Google Scholar 

  209. Schindler T, Sicheri F, Pico A et al (1999) Crystal structure of Hck in complex with a Src family-selective tyrosine kinase inhibitor. Mol Cell 3:639–648

    Article  CAS  Google Scholar 

  210. Zhu X, Kim JL, Newcomb JR et al (1999) Structural analysis of the lymphocyte-specific kinase Lck in complex with non-selective and Src family selective kinase inhibitors. Structure 7:651–661

    Article  CAS  Google Scholar 

  211. Vignaroli G, Mencarelli M, Sementa D et al (2014) Exploring the chemical space around the privileged pyrazolo[3,4-d]pyrimidine scaffold: toward novel allosteric inhibitors of T315I-mutated Abl. ACS Comb Sci 16:168–175

    Article  CAS  Google Scholar 

  212. Smith B, Medda F, Gokhale V et al (2012) Recent advances in the design, synthesis, and biological evaluation of selective DYRK1A inhibitors: a new avenue for a disease modifying treatment of Alzheimer's? ACS Chem Neurosci 3:857–872

    Article  CAS  Google Scholar 

  213. Agholme L, Lindstrom T, Kagedal K et al (2010) An in vitro model for neuroscience: differentiation of SH-SY5Y cells into cells with morphological and biochemical characteristics of mature neurons. J Alzheimers Dis 20:1069–1082

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100, Siena, Italy

    Anna Lucia Fallacara, Iuni Margaret Laura Trist & Maurizio Botta

  2. Dipartimento di Farmacia, Università degli Studi di Genova, Viale Benedetto XV, 3, 16132, Genoa, Italy

    Silvia Schenone

  3. Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, BioLife Science Building, Suite 333, 1900 N 12th Street, Philadelphia, PA, 19122, USA

    Maurizio Botta

Authors
  1. Anna Lucia Fallacara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Iuni Margaret Laura Trist
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Silvia Schenone
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maurizio Botta
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Maurizio Botta .

Editor information

Editors and Affiliations

  1. Department of Medicinal Chemistry, University of Kansas , Lawrence, Kansas, USA

    Michael S. Wolfe

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Fallacara, A.L., Trist, I.M.L., Schenone, S., Botta, M. (2017). Inhibitors of Tau-Phosphorylating Kinases. In: Wolfe, M. (eds) Alzheimer’s Disease II. Topics in Medicinal Chemistry, vol 24. Springer, Cham. https://doi.org/10.1007/7355_2016_17

Download citation

Publish with us

Policies and ethics

Search

Navigation