Skip to main content
SpringerLink
Log in

The Role of Tissue Non-specific Alkaline Phosphatase (TNAP) in Neurodegenerative Diseases: Alzheimer’s Disease in the Focus

  • Chapter
  • First Online:
Book cover Neuronal Tissue-Nonspecific Alkaline Phosphatase (TNAP)

Part of the book series: Subcellular Biochemistry ((SCBI,volume 76))

Abstract

Tissue non-specific alkaline phosphatase (TNAP) is present on neuronal membranes and induces neuronal toxicity via tau dephosphorylation; a mechanism which could play a role in the neuronal loss seen in Alzheimer’s disease (AD). TNAP increases in the plasma following brain injury and cerebrovascular disease. In this chapter we summarise our previous work which looked at changes in TNAP activity in the brain and plasma of AD individuals and discuss whether these changes may be reflective of neuronal loss. Our data demonstrate that TNAP activity is significantly increased in the brain in both the sporadic and familial forms of AD and that TNAP activity is significantly increased in the plasma in AD patients. In addition, we describe a significant inverse correlation between plasma TNAP activity and cognitive function in AD. Using these data we propose a model for TNAP-induced neurodegeneration in AD resulting from tau dephosphorylation following secretion of tau from neuronal cells.

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

References

  • Bertram L, Tanzi RE (2010) Alzheimer disease: new light on an old CLU. Nat Rev Neurol 6(1):11–13

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82(4):239–259

    Article  CAS  PubMed  Google Scholar 

  • Brayne C (2007) The elephant in the room—healthy brains in later life, epidemiology and public health. Nat Rev Neurosci 8(3):233–239

    Article  CAS  PubMed  Google Scholar 

  • Burns A, Iliffe S (2009) Alzheimer’s disease. BMJ 338:b158

    Article  PubMed  Google Scholar 

  • Cacabelos R, Fernandez-Novoa L, Corzo L, Amado L, Pichel V, Lombardi V, Kubota Y (2004) Phenotypic profiles and functional genomics in Alzheimer’s disease and in dementia with a vascular component. Neurol Res 26(5):459–480

    Article  CAS  PubMed  Google Scholar 

  • Carrasquillo MM, Belbin O, Hunter TA, Ma L, Bisceglio GD, Zou F, Crook JE, Pankratz VS, Sando SB, Aasly JO, Barcikowska M, Wszolek ZK, Dickson DW, Graff-Radford NR, Petersen RC, Morgan K, Younkin SG (2011) Replication of BIN1 association with Alzheimer’s disease and evaluation of genetic interactions. JAD 24(4):751–758

    CAS  PubMed Central  PubMed  Google Scholar 

  • Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A, Fraser G, Stalder AK, Beibel M, Staufenbiel M, Jucker M, Goedert M, Tolnay M (2009) Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 11(7):909–913

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Cras P, Smith MA, Richey PL, Siedlak SL, Mulvihill P, Perry G (1995) Extracellular neurofibrillary tangles reflect neuronal loss and provide further evidence of extensive protein cross-linking in Alzheimer disease. Acta Neuropathol 89(4):291–295

    Article  CAS  PubMed  Google Scholar 

  • de Calignon A, Polydoro M, Suarez-Calvet M, William C, Adamowicz DH, Kopeikina KJ, Pitstick R, Sahara N, Ashe KH, Carlson GA, Spires-Jones TL, Hyman BT (2012) Propagation of tau pathology in a model of early Alzheimer’s disease. Neuron 73(4):685–697

    Article  PubMed Central  PubMed  Google Scholar 

  • Diaz-Hernandez M, Gomez-Ramos A, Rubio A, Gomez-Villafuertes R, Naranjo JR, Miras-Portugal MT, Avila J (2010) Tissue-nonspecific alkaline phosphatase promotes the neurotoxicity effect of extracellular tau. J Biol Chem 285(42):32539–32548

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Diez-Zaera M, Diaz-Hernandez JI, Hernandez-Alvarez E, Zimmermann H, Diaz-Hernandez M, Miras-Portugal MT (2011) Tissue-nonspecific alkaline phosphatase promotes axonal growth of hippocampal neurons. Mol Biol Cell 22(7):1014–1024

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Folstein MF, Folstein SE, McHugh PR (1975) Mini-mental state. a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12(3):189–198

    Article  CAS  PubMed  Google Scholar 

  • Fonta C, Negyessy L, Renaud L, Barone P (2004) Areal and subcellular localization of the ubiquitous alkaline phosphatase in the primate cerebral cortex: evidence for a role in neurotransmission. Cereb Cortex 14(6):595–609

    Article  PubMed  Google Scholar 

  • Frost B, Jacks RL, Diamond MI (2009) Propagation of tau misfolding from the outside to the inside of a cell. J Biol Chem 284(19):12845–12852

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gomez-Ramos A, Diaz-Hernandez M, Rubio A, Miras-Portugal MT, Avila J (2008) Extracellular tau promotes intracellular calcium increase through M1 and M3 muscarinic receptors in neuronal cells. Mol Cell Neurosci 37(4):673–681

    Article  CAS  PubMed  Google Scholar 

  • Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Williams A, Jones N, Thomas C, Stretton A, Morgan AR, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Morgan K, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Love S, Kehoe PG, Hardy J, Mead S, Fox N, Rossor M, Collinge J, Maier W, Jessen F, Schurmann B, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frolich L, Hampel H, Hull M, Rujescu D, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Sleegers K, Bettens K, Engelborghs S, De Deyn PP, Van Broeckhoven C, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Guerreiro R, Muhleisen TW, Nothen MM, Moebus S, Jockel KH, Klopp N, Wichmann HE, Carrasquillo MM, Pankratz VS, Younkin SG, Holmans PA, O’Donovan M, Owen MJ, Williams J (2009) Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet 41(10):1088–1093

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hollingworth P, Harold D, Sims R, Gerrish A, Lambert JC, Carrasquillo MM, Abraham R, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Jones N, Stretton A, Thomas C, Richards A, Ivanov D, Widdowson C, Chapman J, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Beaumont H, Warden D, Wilcock G, Love S, Kehoe PG, Hooper NM, Vardy ER, Hardy J, Mead S, Fox NC, Rossor M, Collinge J, Maier W, Jessen F, Ruther E, Schurmann B, Heun R, Kolsch H, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frolich L, Hampel H, Gallacher J, Hull M, Rujescu D, Giegling I, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Sleegers K, Bettens K, Engelborghs S, De Deyn PP, Van Broeckhoven C, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Guerreiro R, Muhleisen TW, Nothen MM, Moebus S, Jockel KH, Klopp N, Wichmann HE, Pankratz VS, Sando SB, Aasly JO, Barcikowska M, Wszolek ZK, Dickson DW, Graff-Radford NR, Petersen RC, van Duijn CM, Breteler MM, Ikram MA, DeStefano AL, Fitzpatrick AL, Lopez O, Launer LJ, Seshadri S, Berr C, Campion D, Epelbaum J, Dartigues JF, Tzourio C, Alperovitch A, Lathrop M, Feulner TM, Friedrich P, Riehle C, Krawczak M, Schreiber S, Mayhaus M, Nicolhaus S, Wagenpfeil S, Steinberg S, Stefansson H, Stefansson K, Snaedal J, Bjornsson S, Jonsson PV, Chouraki V, Genier-Boley B, Hiltunen M, Soininen H, Combarros O, Zelenika D, Delepine M, Bullido MJ, Pasquier F, Mateo I, Frank-Garcia A, Porcellini E, Hanon O, Coto E, Alvarez V, Bosco P, Siciliano G, Mancuso M, Panza F, Solfrizzi V, Nacmias B, Sorbi S, Bossu P, Piccardi P, Arosio B, Annoni G, Seripa D, Pilotto A, Scarpini E, Galimberti D, Brice A, Hannequin D, Licastro F, Jones L, Holmans PA, Jonsson T, Riemenschneider M, Morgan K, Younkin SG, Owen MJ, O’Donovan M, Amouyel P, Williams J (2011) Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat Genet 43(5):429–435

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Holmes BB, Devos SL, Kfoury N, Li M, Jacks R, Yanamandra K, Ouidja MO, Brodsky FM, Marasa J, Bagchi DP, Kotzbauer PT, Miller TM, Papy-Garcia D, Diamond MI (2013) Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds. PNAS 110(33):E3138–E3147

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hu X, Pickering EH, Hall SK, Naik S, Liu YC, Soares H, Katz E, Paciga SA, Liu W, Aisen PS, Bales KR, Samad TA,John SL (2011) Genome-wide association study identifies multiple novel loci associated with disease progression in subjects with mild cognitive impairment. Transl Psychiatry 1:e54

    Google Scholar 

  • Iqbal K, Alonso Adel C, Chen S, Chohan MO, El-Akkad E, Gong CX, Khatoon S, Li B, Liu F, Rahman A, Tanimukai H, Grundke-Iqbal I (2005) Tau pathology in Alzheimer disease and other tauopathies. Biochim Biophys Acta 1739(2–3):198–210

    Article  CAS  PubMed  Google Scholar 

  • Kellett KA, Williams J, Vardy ER, Smith AD, Hooper NM (2011) Plasma alkaline phosphatase is elevated in Alzheimer’s disease and inversely correlates with cognitive function. Int J Mol Epidemiol Genet 2(2):114–121

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lampl Y, Paniri Y, Eshel Y, Sarova-Pinchas I (1990) Alkaline phosphatase level in CSF in various brain tumors and pulmonary carcinomatous meningitis. J Neurooncol 9(1):35–40

    Article  CAS  PubMed  Google Scholar 

  • Liu L, Drouet V, Wu JW, Witter MP, Small SA, Clelland C, Duff K (2012) Trans-synaptic spread of tau pathology in vivo. PLoS ONE 7(2):e31302

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Matthews FE, McKeith I, Bond J, Brayne C (2007) Reaching the population with dementia drugs: what are the challenges? Int J Geriatr Psychiatry 22(7):627–631

    Article  PubMed  Google Scholar 

  • McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (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(7):939–944

    Article  CAS  PubMed  Google Scholar 

  • Meythaler JM, Hazlewood J, DeVivo MJ, Rosner M (1998) Elevated liver enzymes after nontraumatic intracranial hemorrhages. Arch Phys Med Rehabil 79(7):766–771

    Article  CAS  PubMed  Google Scholar 

  • Morgan K (2011) The three new pathways leading to Alzheimer’s disease. Neuropathol Appl Neurobiol 37(4):353–357

    Article  CAS  PubMed  Google Scholar 

  • Mullan M, Crawford F, Axelman K, Houlden H, Lilius L, Winblad B, Lannfelt L (1992) A pathogenic mutation for probable Alzheimer’s disease in the APP gene at the N-terminus of beta-amyloid. Nat Genet 1(5):345–347

    Article  CAS  PubMed  Google Scholar 

  • Negyessy L, Xiao J, Kantor O, Kovacs GG, Palkovits M, Doczi TP, Renaud L, Baksa G, Glasz T, Ashaber M, Barone P, Fonta C (2011) Layer-specific activity of tissue non-specific alkaline phosphatase in the human neocortex. Neuroscience 172:406–418

    Article  CAS  PubMed  Google Scholar 

  • Pimplikar SW (2009) Reassessing the amyloid cascade hypothesis of Alzheimer’s disease. Int J Biochem Cell Biol 41(6):1261–1268

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Roth M, Tym E, Mountjoy CQ, Huppert FA, Hendrie H, Verma S, Goddard R (1986) CAMDEX. A standardised instrument for the diagnosis of mental disorder in the elderly with special reference to the early detection of dementia. British J Psych 149:698–709

    Article  CAS  Google Scholar 

  • Seshadri S, Fitzpatrick AL, Ikram MA, DeStefano AL, Gudnason V, Boada M, Bis JC, Smith AV, Carassquillo MM, Lambert JC, Harold D, Schrijvers EM, Ramirez-Lorca R, Debette S, Longstreth WT Jr, Janssens AC, Pankratz VS, Dartigues JF, Hollingworth P, Aspelund T, Hernandez I, Beiser A, Kuller LH, Koudstaal PJ, Dickson DW, Tzourio C, Abraham R, Antunez C, Du Y, Rotter JI, Aulchenko YS, Harris TB, Petersen RC, Berr C, Owen MJ, Lopez-Arrieta J, Varadarajan BN, Becker JT, Rivadeneira F, Nalls MA, Graff-Radford NR, Campion D, Auerbach S, Rice K, Hofman A, Jonsson PV, Schmidt H, Lathrop M, Mosley TH, Au R, Psaty BM, Uitterlinden AG, Farrer LA, Lumley T, Ruiz A, Williams J, Amouyel P, Younkin SG, Wolf PA, Launer LJ, Lopez OL, van Duijn CM, Breteler MM (2010) Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA 303(18):1832–1840

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Street SE, Kramer NJ, Walsh PL, Taylor-Blake B, Yadav MC, King IF, Vihko P, Wightman RM, Millan JL, Zylka MJ (2013) Tissue-Nonspecific alkaline phosphatase acts redundantly with PAP and NT5E to generate adenosine in the dorsal spinal cord. J Neurosci 33(27):11314–11322

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Vardy ER, Kellett KA, Cocklin SL, Hooper NM (2012) Alkaline phosphatase is increased in both brain and plasma in Alzheimer’s disease. Neurodegener Dis 9(1):31–37

    Article  CAS  PubMed  Google Scholar 

  • Wijsman EM, Pankratz ND, Choi Y, Rothstein JH, Faber KM, Cheng R, Lee JH, Bird TD, Bennett DA, Diaz-Arrastia R, Goate AM, Farlow M, Ghetti B, Sweet RA, Foroud TM, Mayeux R (2011) Genome-wide association of familial late-onset Alzheimer’s disease replicates BIN1 and CLU and nominates CUGBP2 in interaction with APOE. PLoS Genet 7(2):e1001308

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yamashita M, Sasaki M, Mii K, Tsuzuki M, Takakura K, Yoshinoya S, Ohkubo A (1989) Measurement of serum alkaline phosphatase isozyme I in brain-damaged patients. Neurol Med Chir (Tokyo) 29(11):995–998

    Article  CAS  Google Scholar 

  • Zhou B, Liu Y, Zhang Z, An N, Yao H, Wang P, Wang L, Zhang X, Jiang T (2013) Impaired functional connectivity of the thalamus in alzheimer’s disease and mild cognitive impairment: a resting-state FMRI study. Curr Alzheimer Res 10(7):754–766

    Article  CAS  PubMed  Google Scholar 

Download references

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Author information

Authors and Affiliations

  1. Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Manchester, M13 9PT, UK

    Katherine A. B. Kellett & Nigel M. Hooper

Authors
  1. Katherine A. B. Kellett
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nigel M. Hooper
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Katherine A. B. Kellett .

Editor information

Editors and Affiliations

  1. National Centre for Scientific Research (CNRS), University of Toulouse-UPS, Toulouse, France

    Caroline Fonta

  2. Wigner Research Centre for Physics, Hungarian Academy of Sciences, Budapest, Hungary

    László Négyessy

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer Science+Business Media Dordrecht

About this chapter

Cite this chapter

Kellett, K.A.B., Hooper, N.M. (2015). The Role of Tissue Non-specific Alkaline Phosphatase (TNAP) in Neurodegenerative Diseases: Alzheimer’s Disease in the Focus. In: Fonta, C., Négyessy, L. (eds) Neuronal Tissue-Nonspecific Alkaline Phosphatase (TNAP). Subcellular Biochemistry, vol 76. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-7197-9_17

Download citation

Publish with us

Policies and ethics

Search

Navigation