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α-Secretase ADAM10 as Well as αAPPs Is Reduced in Platelets and CSF of Alzheimer Disease Patients

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Abstract

Background

Members of membrane-bound disintegrin metalloproteinases (ADAMs) were shown to be capable of cleaving amyloid precursor protein (APP) at the α-cleavage site in different cell systems. One of the candidate α-secretases identified in this family is ADAM10. The present study addresses the following major questions: 1) Are the levels of an α-secretase candidate (i.e., ADAM10) reduced in accessible cells of Alzheimer Disease (AD) patients? 2) Are ADAM10 levels in the peripheral cells of AD patients related to a concomitant decrease in αAPPs?

Materials and Methods

Western Blot analysis of ADAM10 is performed on platelet homogenates from 33 sporadic AD patients and on 26 age-matched control subjects. Moreover, the levels of α-secretase metabolite (αAPPs) are tested both in platelets and cerebrospinal fluid (CSF) of the same pool of subjects by means of Western blot with a specific antibody.

Results

A significant decrease of platelet ADAM10 levels is observed in patients affected by probable AD when compared to control subjects and this is paralleled by a reduced level of αAPPs released from platelets. Moreover, in the same pool of AD patients, αAPPs levels were reduced concomitantly in CSF.

Conclusions

ADAM10 is expressed in platelets. A reduced level of ADAM10 is observed in platelets obtained from AD patients compared to age-matched controls. Further, in the same pool of AD patients, a qualitatively and quantitatively similar decrease in αAPPs is present both in thrombin-activated platelets and CSF, thus suggesting that alterations of APP processing might occur both in the neuronal compartment and peripheral cells.

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References

  1. Sisodia SS. (1992) Beta-amyloid precursor protein cleavage by a membrane-bound protease. Proc. Natl. Acad. Sci. U.S.A. 89: 6075–6079.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Tomita S, Kirino Y, Suzuki T. (1998) Cleavage of Alzheimer’s amyloid precursor protein (APP) by secretases occurs after O-glycosylation of APP in the protein secretory pathway—Identification of intracellular compartment in which APP cleavage occurs without using toxic agents that interfere with protein metabolism. J. Biol. Chem. 273: 6277–6284.

    Article  CAS  PubMed  Google Scholar 

  3. Weidemann A, Konig G, Bunke D, et al. (1989) Identification, biogenesis, and localization of precursors of Alzheimer’s disease A4 amyloid protein. Cell 57: 115–126.

    Article  CAS  PubMed  Google Scholar 

  4. Haass C, Selkoe DJ. (1993) Cellular processing of beta-amyloid precursor protein and the genesis of amyloid beta-peptide. Cell 75: 1039–1042.

    Article  CAS  PubMed  Google Scholar 

  5. Walter J, Capell A, Hung AY, et al. (1997) Ectodomain phosphorylation of beta-amyloid precursor protein at two distinct cellular locations. J. Biol. Chem. 272: 1896–1903.

    Article  CAS  PubMed  Google Scholar 

  6. Buxbaum JD, Liu KN, Luo X, et al. (1998) Evidence that tumor necrosis factor alpha-converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid precursor protein. J. Biol. Chem. 273: 27765–27767.

    Article  CAS  PubMed  Google Scholar 

  7. Nitsch RM, Slack BE, Wurtman RJ, et al. (1992) Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors. Science 258: 304–307.

    Article  CAS  PubMed  Google Scholar 

  8. Koike H, Tomioka S, Sorimachi H, et al. (1999) Membrane-anchored metalloprotease MDC9 has an alpha-secretase activity responsible for processing the amyloid precursor protein. Biochem. J. 343: 371–375.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Nelson KK, Schlondorff J, Blobel CP. (1999) Evidence for an interaction of the metalloprotease-disintegrin tumor necrosis factor alpha convertase (TACE) with mitotic arrest deficient 2 (MAD2), and of the metalloprotease-disintegrin MDC9 with a novel MAD2-related protein, MAD2beta. Biochem. J. 343: 673–680.

    PubMed  PubMed Central  CAS  Google Scholar 

  10. Lammich S, Kojro E, Postina R, et al. (1999) Constitutive and regulated α-secretase cleavage of Alzheimer’s amyloid precursor protein by a disintegrin metalloprotease. Proc. Natl. Acad. Sci. U.S.A. 96: 3922–3927.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kojro E, Giml G, Lammich S, Marz W, Fahrenholz F. (2001) Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the α-secretase. Proc. Natl. Acad. Sci. U.S.A. 98: 5815–5820.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Slack BE, Ma LK, Seah CC. (2001) Constitutive shedding of the amyloid precursor protein ectodomain is up-regulated by tumour necrosis factor-alpha converting enzyme. Biochem. J. 357: 787–794.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Parvathy S, Hussain I, Karran EH, Turner AJ, Hooper NM. (1998) Alzheimer’s amyloid precursor protein alpha-secretase is inhibited by hydroxamic acid-based zinc metalloprotease inhibitors: Similarities to the angiotensin converting enzyme secretase. Biochemistry 37: 1680–1685.

    Article  CAS  PubMed  Google Scholar 

  14. Di Luca M, Pastorino L, Cattabeni F, et al. (1996) Abnormal pattern of platelet APP isoforms in Alzheimer disease and Down syndrome. Arch. Neurol. 53: 1162–1166.

    Article  PubMed  Google Scholar 

  15. Davies TA, Long HJ, Tibbles HE, et al. (1997) Moderate and advanced Alzheimer’s patients exhibit platelet activation differences. Neurobiol. Aging 18: 155–162.

    Article  CAS  PubMed  Google Scholar 

  16. Davies TA, Long HJ, Sgro K. (1997) Activated Alzheimer disease platelets retain more beta amyloid precursor protein. Neurobiol. Aging 18: 147–153.

    Article  CAS  PubMed  Google Scholar 

  17. Rosenberg RN, Baskin F, Fosmire JA, et al. (1997) Altered amyloid protein processing in platelets of patients with Alzheimer disease. Arch. Neurol. 54: 139–144.

    Article  CAS  PubMed  Google Scholar 

  18. Bush AI, Tanzi RE. (1998) Alzheimer disease-related abnormalities of amyloid beta precursor protein isoforms in the platelets—the brain delegates in the periphery? Arch. Neurol. 55: 1179–1180.

    Article  CAS  PubMed  Google Scholar 

  19. Di Luca M, Pastorino L, Bianchetti A, et al. (1998) Differential pattern of platelet APP isoforms: An early marker for Alzheimer disease. Arch. Neurol. 55: 1195–1200.

    Article  PubMed  Google Scholar 

  20. Baskin F, Rosenberg RN, Iyer L, et al. (2000) Platelet APP isoform ratios correlate with declining cognition in AD. Neurology 54: 1907–1909.

    Article  CAS  PubMed  Google Scholar 

  21. Borroni B, Colciaghi F, Pastorino L, et al. (2001) Amyloid precursor protein in platelets of patients with Alzheimer disease—Effect of acetylcholinesterase inhibitor treatment. Arch. Neurol. 58: 442–446.

    Article  CAS  PubMed  Google Scholar 

  22. Padovani L, Pastorino B, Borroni et al. (In press) Amyloid precursor protein in platelets: A peripheral marker for the diagnosis of sporadic AD. Neurology.

  23. Van Nostrand WE, Schmaier AH, Farrow JS, Cunningham DD. (1990) Protease nexin II (amyloid beta protein precursor): A platelet α-granule protein. Science 248: 745–748.

    Article  PubMed  Google Scholar 

  24. Li QX, Whyte S, Tanner JE, et al. (1998) Secretion of Alzheimer’s disease A beta amyloid peptide by activated human platelets. Lab. Invest. 78: 461–469.

    PubMed  CAS  Google Scholar 

  25. Abraham CR, Marshall DC, Tibbles HE, et al. (1999) Platelets and DAMI megakaryocytes possess beta-secretase-like activity. J. Lab. Clin. Med. 133: 507–515.

    Article  CAS  PubMed  Google Scholar 

  26. Bush AI, Martins RN, Rumble B, et al. (1990) The amyloid precursor protein of Alzheimer’s disease is released by human platelets. J. Biol. Chem. 265: 15977–15983.

    PubMed  CAS  Google Scholar 

  27. Lannfelt L, Basun H, Wahlund LO, et al. (1995) Decreased alpha-secretase-cleaved amyloid precursor protein as a diagnostic marker for Alzheimer’s disease. Nat. Med. 1: 829–832.

    Article  CAS  PubMed  Google Scholar 

  28. Almkvist O, Basun H, Wagner S, et al. (1997) Cerebrospinal fluid levels of alpha-secretase-cleaved soluble amyloid precursor protein mirror cognition in a Swedish family with Alzheimer disease and a gene mutation. Arch. Neurol. 54: 641–644.

    Article  CAS  PubMed  Google Scholar 

  29. Sennvik K, Fastbom J, Blomberg M, et al. (20000 Levels of a and β secretase cleaved amyloid precursor protein in the cerebrospinal fluid of Alzheimer’s disease patients. Neurosci. Lett. 278: 169–172.

  30. Marcinkiewicz M, Seidah NG. (2000) Coordinated expression of β-amyloid precursor protein and putative β-secretase BACE and α-secretase ADAM10 in mouse and human brain. J. Neurochem. 75: 2133–2143.

    Article  CAS  PubMed  Google Scholar 

  31. Skovronsky DM, Lee VMY, Praticò D. (2001) Amyloid precursor protein and amyloid b peptide in human platelets. J. Biol. Chem. 286: 17036–17043.

    Article  Google Scholar 

  32. Ferrarese C, Begni B, Canevari C, et al. (2000) L. Glutamate uptake is decreased in platelets from Alzheimer’s disease patients. Ann. Neurol. 47: 641–643.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work is supported by CNR grants # 98.01097.CT14 and # 99.01234.CT14 to M.D.L., MURST 40% 1999–2000, N° 9906158271-004 to M.D.L., and Progetto Alzheimer Min. Sanita’2001–2003 to F.C. and M.D.L.

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Authors and Affiliations

  1. Centre of Excellence on Neurodegenerative Diseases and Department of Pharmacological Sciences, University of Milano, School of Pharmacy, Via Balzaretti, 9, 20133, Milano, Italy

    Francesca Colciaghi, Lucia Pastorino, Elena Marcello, Martina Zimmermann, Flaminio Cattabeni & Monica Di Luca PhD

  2. Department of Medical Sciences-Neurology Unit, University of Brescia School of Medicine, Brescia, Italy

    Barbara Borroni & Alessandro Padovani

Authors
  1. Francesca Colciaghi
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  2. Barbara Borroni
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  3. Lucia Pastorino
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  4. Elena Marcello
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  5. Martina Zimmermann
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  6. Flaminio Cattabeni
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  7. Alessandro Padovani
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  8. Monica Di Luca PhD
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Correspondence to Monica Di Luca PhD.

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Colciaghi, F., Borroni, B., Pastorino, L. et al. α-Secretase ADAM10 as Well as αAPPs Is Reduced in Platelets and CSF of Alzheimer Disease Patients. Mol Med 8, 67–74 (2002). https://doi.org/10.1007/BF03402076

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  • DOI: https://doi.org/10.1007/BF03402076

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