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Serum beta-secretase 1 (BACE1) activity as candidate biomarker for late-onset Alzheimer’s disease

  • Carlo CervellatiEmail author
  • Alessandro Trentini
  • Valentina Rosta
  • Angelina Passaro
  • Cristina Bosi
  • Juana Maria Sanz
  • Stefania Bonazzi
  • Salvatore Pacifico
  • Davide Seripa
  • Giuseppe Valacchi
  • Remo Guerini
  • Giovanni Zuliani
Original Article

Abstract

Beta-secretase (BACE1) is a key enzyme in the formation of amyloid-β; its activity/concentration is increased in brain and cerebrospinal fluid of patients with late-onset Alzheimer’s disease (LOAD). Since BACE1 was found also in blood, we evaluated its potential as peripheral biomarker. To this aim, serum BACE1 activity was assessed in 115 subjects with LOAD and 151 controls. We found that BACE1 changed across groups (p < 0.001) with a 25% increase in LOAD versus controls. High levels of BACE1 (IV quartile) were independently associated with the diagnosis of LOAD (OR 2.8; 1.4–5.7). Diagnostic accuracy was 76% for LOAD. Our data suggest that increased BACE1 activity in serum may represent a potential biomarker for LOAD. Additional studies are needed to confirm the usefulness of BACE1, alone or in combination with other markers, in discriminating patients and predicting LOAD onset and progression.

Keywords

Late-onset Alzheimer’s disease Mild cognitive impairment Mixed dementia Blood-based biomarkers BACE1 

Notes

Acknowledgments

We would like to thank Dr Arianna Romani for helping in the assay optimization.

Funding information

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

11357_2019_127_MOESM1_ESM.docx (606 kb)
ESM 1 (DOCX 605 kb)

References

  1. Baazaoui N, Iqbal K (2018) A novel therapeutic approach to treat Alzheimer’s disease by neurotrophic support during the period of synaptic compensation. J Alzheimers Dis 62:1211–1218CrossRefGoogle Scholar
  2. Bodendorf U, Danner S, Fischer F, Stefani M, Sturchler-Pierrat C, Wiederhold KH, Staufenbiel M, Paganetti P (2002) Expression of human beta-secretase in the mouse brain increases the steady-state level of beta-amyloid. J Neurochem 80:799–806CrossRefGoogle Scholar
  3. Bruford E, Lush MJ, Wright MW, Sneddon TP, Povey S, Birney E (2008) The HGNC database in 2008: a resource for the human genome. Nucleic Acids Res 36:D445–D448CrossRefGoogle Scholar
  4. Butterfield DA, Poon HF, St. Clair D et al (2006) Redox proteomics identification of oxidatively modified hippocampal proteins in mild cognitive impairment: insights into the development of Alzheimer’s disease. Neurobiol Dis 22:223–232CrossRefGoogle Scholar
  5. Cervellati C, Cremonini E, Bosi C, Magon S, Zurlo A, Bergamini CM, Zuliani G (2013) Systemic oxidative stress in older patients with mild cognitive impairment or late onset Alzheimer’s disease. Curr Alzheimer Res 10:365–372CrossRefGoogle Scholar
  6. Cervellati C, Romani A, Seripa D, Cremonini E, Bosi C, Magon S, Passaro A, Bergamini CM, Pilotto A, Zuliani G (2014a) Oxidative balance, homocysteine, and uric acid levels in older patients with late onset Alzheimer’s disease or vascular dementia. J Neurol Sci 337:156–161CrossRefGoogle Scholar
  7. Cervellati C, Romani A, Seripa D et al (2014b) Systemic oxidative stress and conversion to dementia of elderly patients with mild cognitive impairment. Biomed Res Int 2014:309507PubMedPubMedCentralGoogle Scholar
  8. Cervellati C, Romani A, Bergamini CM, Bosi C, Sanz JM, Passaro A, Zuliani G (2015) PON-1 and ferroxidase activities in older patients with mild cognitive impairment, late onset Alzheimer’s disease or vascular dementia. Clin Chem Lab Med 53:1049–1056CrossRefGoogle Scholar
  9. Cervellati C, Wood PL, Romani A, Valacchi G, Squerzanti M, Sanz JM, Ortolani B, Zuliani G (2016) Oxidative challenge in Alzheimer’s disease: state of knowledge and future needs. J Investig Med 64:21–32CrossRefGoogle Scholar
  10. Chen L, Na R, Gu M, Richardson A, Ran Q (2008) Lipid peroxidation up-regulates BACE1 expression in vivo: a possible early event of amyloidogenesis in Alzheimer’s disease. J Neurochem 107:197–207CrossRefGoogle Scholar
  11. Decourt B, Sabbagh MN (2011) BACE1 as a potential biomarker for Alzheimer’s disease. J Alzheimers Dis 24:53–59CrossRefGoogle Scholar
  12. Fukumoto H, Cheung BS, Hyman BT, Irizarry MC (2002) Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease. Arch Neurol 59:1381–1389CrossRefGoogle Scholar
  13. Grüninger-Leitch F, Schlatter D, Küng E, Nelböck P, Döbeli H (2002) Substrate and inhibitor profile of BACE (beta-secretase) and comparison with other mammalian aspartic proteases. J Biol Chem 277:4687–4693CrossRefGoogle Scholar
  14. Guglielmotto M, Aragno M, Autelli R, Giliberto L, Novo E, Colombatto S, Danni O, Parola M, Smith MA, Perry G, Tamagno E, Tabaton M (2009) The up-regulation of BACE1 mediated by hypoxia and ischemic injury: role of oxidative stress and HIF1α. J Neurochem 108:1045–1056CrossRefGoogle Scholar
  15. Johnston JA, Liu WW, Coulson DTR, Todd S, Murphy S, Brennan S, Foy CJ, Craig D, Irvine GB, Passmore AP (2008) Platelet β-secretase activity is increased in Alzheimer’s disease. Neurobiol Aging 29:661–668CrossRefGoogle Scholar
  16. Liu WW, Todd S, Coulson DTR, Irvine GB, Passmore AP, McGuinness B, McConville M, Craig D, Johnston JA (2009) A novel reciprocal and biphasic relationship between membrane cholesterol and beta-secretase activity in SH-SY5Y cells and in human platelets. J Neurochem 108:341–349CrossRefGoogle Scholar
  17. Luo Y, Bolon B, Kahn S, Bennett BD, Babu-Khan S, Denis P, Fan W, Kha H, Zhang J, Gong Y, Martin L, Louis JC, Yan Q, Richards WG, Citron M, Vassar R (2001) Mice deficient in BACE1, the Alzheimer’s beta-secretase, have normal phenotype and abolished beta-amyloid generation. Nat Neurosci 4:231–232CrossRefGoogle Scholar
  18. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, Klunk WE, Koroshetz WJ, Manly JJ, Mayeux R, Mohs RC, Morris JC, Rossor MN, Scheltens P, Carrillo MC, Thies B, Weintraub S, Phelps CH (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 7:263–269CrossRefGoogle Scholar
  19. Morris JK, Honea RA, Vidoni ED, Swerdlow RH, Burns JM (2014) Is Alzheimer’s disease a systemic disease? Biochim Biophys Acta 1842:1340–1349CrossRefGoogle Scholar
  20. Mouton-Liger F, Paquet C, Dumurgier J, Bouras C, Pradier L, Gray F, Hugon J (2012) Oxidative stress increases BACE1 protein levels through activation of the PKR-eIF2α pathway. Biochim Biophys Acta 1822:885–896CrossRefGoogle Scholar
  21. Schipke CG, De Vos A, Fuentes M et al (2018) Neurogranin and BACE1 in CSF as potential biomarkers differentiating depression with cognitive deficits from early Alzheimer’s disease: a pilot study. Dement Geriatr Cogn Dis Extra 8:277–289CrossRefGoogle Scholar
  22. Schrag M, Mueller C, Zabel M, Crofton A, Kirsch WM, Ghribi O, Squitti R, Perry G (2013) Oxidative stress in blood in Alzheimer’s disease and mild cognitive impairment: a meta-analysis. Neurobiol Dis 59:100–110CrossRefGoogle Scholar
  23. Shen Y, Wang H, Sun Q, Yao H, Keegan AP, Mullan M, Wilson J, Lista S, Leyhe T, Laske C, Rujescu D, Levey A, Wallin A, Blennow K, Li R, Hampel H (2018) Increased plasma beta-secretase 1 may predict conversion to Alzheimer’s disease dementia in individuals with mild cognitive impairment. Biol Psychiatry 83:447–455CrossRefGoogle Scholar
  24. Smith MA, Richey Harris PL, Sayre LM, Beckman JS, Perry G (1997) Widespread peroxynitrite-mediated damage in Alzheimer’s disease. J Neurosci 17:2653–2657CrossRefGoogle Scholar
  25. Sultana R, Butterfield DA (2009) Oxidatively modified, mitochondria-relevant brain proteins in subjects with Alzheimer disease and mild cognitive impairment. J Bioenerg Biomembr 41:441–446CrossRefGoogle Scholar
  26. Tamagno E, Guglielmotto M, Monteleone D, Tabaton M (2012) Amyloid-β production: major link between oxidative stress and BACE1. Neurotox Res 22:208–219CrossRefGoogle Scholar
  27. Tan J-L, Li Q-X, Ciccotosto GD et al (2013) Mild oxidative stress induces redistribution of BACE1 in non-apoptotic conditions and promotes the amyloidogenic processing of Alzheimer’s disease amyloid precursor protein. PLoS One 8:e61246CrossRefGoogle Scholar
  28. Thambisetty M, Lovestone S (2010) Blood-based biomarkers of Alzheimer’s disease: challenging but feasible. Biomark Med 4:65–79CrossRefGoogle Scholar
  29. Valacchi G, Virgili F, Cervellati C, Pecorelli A (2018) OxInflammation: from subclinical condition to pathological biomarker. Front Physiol 9:858CrossRefGoogle Scholar
  30. Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M (1999) Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286:735–741CrossRefGoogle Scholar
  31. Zetterberg H (2019) Blood-based biomarkers for Alzheimer’s disease—an update. J Neurosci Methods 319:2–6CrossRefGoogle Scholar
  32. Zetterberg H, Andreasson U, Hansson O, Wu G, Sankaranarayanan S, Andersson ME, Buchhave P, Londos E, Umek RM, Minthon L, Simon AJ, Blennow K (2008) Elevated cerebrospinal fluid BACE1 activity in incipient Alzheimer disease. Arch Neurol 65:1102–1107CrossRefGoogle Scholar
  33. Zhong Z, Ewers M, Teipel S, Bürger K, Wallin A, Blennow K, He P, McAllister C, Hampel H, Shen Y (2007) Levels of beta-secretase (BACE1) in cerebrospinal fluid as a predictor of risk in mild cognitive impairment. Arch Gen Psychiatry 64:718–726CrossRefGoogle Scholar

Copyright information

© American Aging Association 2019

Authors and Affiliations

  • Carlo Cervellati
    • 1
    Email author
  • Alessandro Trentini
    • 1
  • Valentina Rosta
    • 1
  • Angelina Passaro
    • 2
  • Cristina Bosi
    • 2
  • Juana Maria Sanz
    • 2
  • Stefania Bonazzi
    • 2
  • Salvatore Pacifico
    • 3
  • Davide Seripa
    • 4
  • Giuseppe Valacchi
    • 1
    • 5
    • 6
  • Remo Guerini
    • 3
  • Giovanni Zuliani
    • 2
  1. 1.Department of Biomedical and Specialist Surgical SciencesUniversity of FerraraFerraraItaly
  2. 2.Department of Morphology, Surgery, and Medical SciencesUniversity of FerraraFerraraItaly
  3. 3.Department of Chemical and Pharmaceutical SciencesUniversity of FerraraFerraraItaly
  4. 4.Research Laboratory, Complex Structure of Geriatrics, Department of Medical SciencesFondazione IRCCS Casa Sollievo della SofferenzaSan Giovanni RotondoItaly
  5. 5.Plants for Human Health Institute, Animal Science DepartmentNC State UniversityKannapolisUSA
  6. 6.Department of Food and NutritionKyung Hee UniversitySeoulRepublic of Korea

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