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Neurotrophin Receptor p75 mRNA Level in Peripheral Blood Cells of Patients with Alzheimer’s Disease

  • Yali Xu
  • Wei-Wei Li
  • Jun Wang
  • Chi Zhu
  • Ying-Ying Shen
  • An-Yu Shi
  • Gui-Hua Zeng
  • Zhi-Qiang Xu
  • Xin-Fu Zhou
  • Yan-Jiang WangEmail author
Original Article

Abstract

The neurotrophin receptor p75 (p75NTR) plays important roles in regulating amyloid-beta (Aβ) metabolism in the brain. The expression of p75NTR is altered in the brain of patients with Alzheimer’s disease (AD). In this study, we aimed to evaluate whether p75NTR mRNA level in the peripheral blood cells is changed among AD patients and its potential to be a biomarker for AD. The study subjects included 26 patients with AD (PiB-PET positive) and 28 cognitively normal controls (PiB-PET negative). RNA was extracted from peripheral blood cells of fast blood. p75NTR mRNA was measured using quantitative real-time PCR assay. p75NTR mRNA levels in blood cells were comparable between AD patients and controls. p75NTR mRNA levels in blood cells were not correlated with MMSE scores, ApoE genotypes, gender, and age. p75NTR mRNA expression in blood cells is not changed in AD patients and is unlikely to be a biomarker for AD.

Keywords

Alzheimer’s disease (AD) mRNA Pittsburgh compound B (PiB) p75 neurotrophin receptor (p75NTR) 

Notes

Funding information

This work was supported by the National Natural Science Foundation of China (grant no. 81625007), China Postdoctoral Science Foundation (2017M623365) and Chongqing Postdoctoral Projects (Xm2017029).

References

  1. Alzheimer’s Disease International, World Health Organization (2012) Dementia: a public health priorityGoogle Scholar
  2. Beach TG, Monsell SE, Phillips LE, Kukull W (2012) Accuracy of the clinical diagnosis of Alzheimer disease at National Institute on Aging Alzheimer Disease Centers, 2005-2010. J Neuropathol Exp Neurol 71:266–273.  https://doi.org/10.1097/NEN.0b013e31824b211b CrossRefGoogle Scholar
  3. Berzi A, Ayata CK, Cavalcante P, Falcone C, Candiago E, Motta T, Bernasconi P, Hohlfeld R, Mantegazza R, Meinl E, Farina C (2008) BDNF and its receptors in human myasthenic thymus: implications for cell fate in thymic pathology. J Neuroimmunol 197:128–139.  https://doi.org/10.1016/j.jneuroim.2008.04.019 CrossRefGoogle Scholar
  4. Braak H, Del Trecidi K (2015) Neuroanatomy and pathology of sporadic Alzheimer’s disease. Adv Anat Embryol Cell Biol 215:1–162CrossRefGoogle Scholar
  5. Bu XL, Yao XQ, Jiao SS, Zeng F, Liu YH, Xiang Y, Liang CR, Wang QH, Wang X, Cao HY, Yi X, Deng B, Liu CH, Xu J, Zhang LL, Gao CY, Xu ZQ, Zhang M, Wang L, Tan XL, Xu X, Zhou HD, Wang YJ (2015) A study on the association between infectious burden and Alzheimer’s disease. Eur J Neurol 22:1519–1525.  https://doi.org/10.1111/ene.12477 CrossRefGoogle Scholar
  6. Bu XL, Xiang Y, Jin WS, Wang J, Shen LL, Huang ZL, Zhang K, Liu YH, Zeng F, Liu JH, Sun HL, Zhuang ZQ, Chen SH, Yao XQ, Giunta B, Shan YC, Tan J, Chen XW, Dong ZF, Zhou HD, Zhou XF, Song W, Wang YJ (2018) Blood-derived amyloid-beta protein induces Alzheimer’s disease pathologies. Mol Psychiatry 23:1–9.  https://doi.org/10.1038/mp.2017.204 CrossRefGoogle Scholar
  7. Chakravarthy B, Menard M, Ito S, Gaudet C, Dal Pra I, Armato U, Whitfield J (2012) Hippocampal membrane-associated p75NTR levels are increased in Alzheimer’s disease. J Alzheimers Dis 30:675–684.  https://doi.org/10.3233/JAD-2012-120115 CrossRefGoogle Scholar
  8. Chao MV (2016) Cleavage of p75 neurotrophin receptor is linked to Alzheimer’s disease. Mol Psychiatry 21:300–301.  https://doi.org/10.1038/mp.2015.214 CrossRefGoogle Scholar
  9. Costantini C, Weindruch R, Della Valle G, Puglielli L (2005) A TrkA to p75 NTR molecular switch activates amyloid beta-peptide generation during aging. Biochem J 391:59–67CrossRefGoogle Scholar
  10. de Wilde A, van der Flier WM, Pelkmans W, Bouwman F, Verwer J, Groot C, van Buchem MM, Zwan M, Ossenkoppele R, Yaqub M, Kunneman M, Smets EMA, Barkhof F, Lammertsma AA, Stephens A, van Lier E, Biessels GJ, van Berckel BN, Scheltens P (2018) Association of amyloid positron emission tomography with changes in diagnosis and patient treatment in an unselected memory clinic cohort: the ABIDE project. JAMA Neurol 75:1062–1070.  https://doi.org/10.1001/jamaneurol.2018.1346 CrossRefGoogle Scholar
  11. Hampel H, O’Bryant SE, Molinuevo JL, Zetterberg H, Masters CL, Lista S, Kiddle SJ, Batrla R, Blennow K (2018) Blood-based biomarkers for Alzheimer disease: mapping the road to the clinic. Nat Rev Neurol 14:639–652.  https://doi.org/10.1038/s41582-018-0079-7 CrossRefGoogle Scholar
  12. Hardy JA, Higgins GA (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science 256:184–185CrossRefGoogle Scholar
  13. Hu XY, Zhang HY, Qin S, Xu H, Swaab DF, Zhou JN (2002) Increased p75(NTR) expression in hippocampal neurons containing hyperphosphorylated tau in Alzheimer patients. Exp Neurol 178:104–111CrossRefGoogle Scholar
  14. Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, Holtzman DM, Jagust W, Jessen F, Karlawish J, Liu E, Molinuevo JL, Montine T, Phelps C, Rankin KP, Rowe CC, Scheltens P, Siemers E, Snyder HM, Sperling R, Elliott C, Masliah E, Ryan L, Silverberg N (2018) NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement 14:535–562.  https://doi.org/10.1016/j.jalz.2018.02.018 CrossRefGoogle Scholar
  15. Jiao SS, Bu XL, Liu YH, Wang QH, Liu CH, Yao XQ, Zhou XF, Wang YJ (2015) Differential levels of p75NTR ectodomain in CSF and blood in patients with Alzheimer’s disease: a novel diagnostic marker. Transl Psychiatry 5:e650.  https://doi.org/10.1038/tp.2015.146 CrossRefGoogle Scholar
  16. Knowles JK, Rajadas J, Nguyen TVV, Yang T, LeMieux MC, Vander Griend L, Ishikawa C, Massa SM, Wyss-Coray T, Longo FM (2009) The p75 neurotrophin receptor promotes amyloid-beta(1-42)-induced neuritic dystrophy in vitro and in vivo. J Neurosci 29:10627–10637.  https://doi.org/10.1523/JNEUROSCI.0620-09.2009 CrossRefGoogle Scholar
  17. Kokaia Z, Andsberg G, Martinez-Serrano A, Lindvall O (1998) Focal cerebral ischemia in rats induces expression of P75 neurotrophin receptor in resistant striatal cholinergic neurons. Neuroscience 84:1113–1125CrossRefGoogle Scholar
  18. Lu R, Wang J, Tao R, Wang J, Zhu T, Guo W, Sun Y, Li H, Gao Y, Zhang W, Fowler CJ, Li Q, Chen S, Wu Z, Masters CL, Zhong C, Jing N, Wang Y, Wang Y (2018) Reduced TRPC6 mRNA levels in the blood cells of patients with Alzheimer’s disease and mild cognitive impairment. Mol Psychiatry 23:767–776.  https://doi.org/10.1038/mp.2017.136 CrossRefGoogle Scholar
  19. Manzine PR, Marcello E, Borroni B, Kamphuis W, Hol E, Padovani A, Nascimento CC, de Godoy Bueno P, Assis Carvalho Vale F, Iost Pavarini SC, di Luca M, Cominetti MR (2015) ADAM10 gene expression in the blood cells of Alzheimer’s disease patients and mild cognitive impairment subjects. Biomarkers 20:196–201.  https://doi.org/10.3109/1354750X.2015.1062554 CrossRefGoogle Scholar
  20. 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 34:939–944CrossRefGoogle Scholar
  21. McKhann GM 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.  https://doi.org/10.1016/j.jalz.2011.03.005 CrossRefGoogle Scholar
  22. Perez SE, He B, Muhammad N, Oh KJ, Fahnestock M, Ikonomovic MD, Mufson EJ (2011) Cholinotrophic basal forebrain system alterations in 3xTg-AD transgenic mice. Neurobiol Dis 41:338–352.  https://doi.org/10.1016/j.nbd.2010.10.002 CrossRefGoogle Scholar
  23. Perini G, Della-Bianca V, Politi V, Della Valle G, Dal-Pra I, Rossi F, Armato U (2002) Role of p75 neurotrophin receptor in the neurotoxicity by beta-amyloid peptides and synergistic effect of inflammatory cytokines. J Exp Med 195:907–918CrossRefGoogle Scholar
  24. Poulopoulou C, Davaki P, Sgouropoulos P, Tsaltas E, Nikolaou C, Orfanioutou F, Vassilopoulos D (2008) Reduced RAGE mRNA in mononuclear blood cells of patients with probable Alzheimer disease. Neurology 70:1571–1573.  https://doi.org/10.1212/01.wnl.0000297196.34007.8a CrossRefGoogle Scholar
  25. Ralainirina N, Brons NH, Ammerlaan W, Hoffmann C, Hentges F, Zimmer J (2010) Mouse natural killer (NK) cells express the nerve growth factor receptor TrkA, which is dynamically regulated. PLoS One 5:e15053.  https://doi.org/10.1371/journal.pone.0015053 CrossRefGoogle Scholar
  26. Rogers ML, Bailey S, Matusica D, Nicholson I, Muyderman H, Pagadala PC, Neet KE, Zola H, Macardle P, Rush RA (2010) ProNGF mediates death of natural killer cells through activation of the p75NTR-sortilin complex. J Neuroimmunol 226:93–103.  https://doi.org/10.1016/j.jneuroim.2010.05.040 CrossRefGoogle Scholar
  27. Saez ET, Pehar M, Vargas MR, Barbeito L, Maccioni RB (2006) Production of nerve growth factor by beta-amyloid-stimulated astrocytes induces p75NTR-dependent tau hyperphosphorylation in cultured hippocampal neurons. J Neurosci Res 84:1098–1106.  https://doi.org/10.1002/jnr.20996 CrossRefGoogle Scholar
  28. Salehi A, Ocampo M, Verhaagen J, Swaab DF (2000) p75 neurotrophin receptor in the nucleus basalis of meynert in relation to age, sex, and Alzheimer’s disease. Exp Neurol 161:245–258CrossRefGoogle Scholar
  29. Shen LL, Mañucat-Tan NB, Gao SH, Li WW, Zeng F, Zhu C, Wang J, Bu XL, Liu YH, Gao CY, Xu ZQ, Bobrovskaya L, Lei P, Yu JT, Song W, Zhou HD, Yao XQ, Zhou XF, Wang YJ (2018) The ProNGF/p75NTR pathway induces tau pathology and is a therapeutic target for FTLD-tau. Mol Psychiatry 23:1813–1824.  https://doi.org/10.1038/s41380-018-0071-z CrossRefGoogle Scholar
  30. Skup M, Bacia A, Koczyk D, Jeglinski W, Zaremba M, Oderfeld-Nowak B (1996) Axonal accumulation of p75NTR and TrkA in the septum following lesion of septo-hippocampal pathways. Acta Neurobiol Exp (Wars) 56:515–525Google Scholar
  31. Sotthibundhu A, Sykes AM, Fox B, Underwood CK, Thangnipon W, Coulson EJ (2008) Beta-amyloid(1-42) induces neuronal death through the p75 neurotrophin receptor. J Neurosci 28:3941–3946.  https://doi.org/10.1523/JNEUROSCI.0350-08.2008 CrossRefGoogle Scholar
  32. Sun BL, Li WW, Zhu C, Jin WS, Zeng F, Liu YH, Bu XL, Zhu J, Yao XQ, Wang YJ (2018) Clinical research on Alzheimer’s disease: progress and perspectives. Neurosci Bull 34:1111–1118.  https://doi.org/10.1007/s12264-018-0249-z CrossRefGoogle Scholar
  33. Wang YJ, Wang X, Lu JJ, Li QX, Gao CY, Liu XH, Sun Y, Yang M, Lim Y, Evin G, Zhong JH, Masters C, Zhou XF (2011) p75NTR regulates Abeta deposition by increasing Abeta production but inhibiting Abeta aggregation with its extracellular domain. J Neurosci 31:2292–2304.  https://doi.org/10.1523/JNEUROSCI.2733-10.2011 CrossRefGoogle Scholar
  34. Wang J, Gu BJ, Masters CL, Wang YJ (2017a) A systemic view of Alzheimer disease - insights from amyloid-beta metabolism beyond the brain. Nat Rev Neurol 13:612–623.  https://doi.org/10.1038/nrneurol.2017.111 CrossRefGoogle Scholar
  35. Wang QH, Wang X, Bu XL, Lian Y, Xiang Y, Luo HB, Zou HQ, Pu J, Zhou ZH, Cui XP, Wang QS, Shi XQ, Han W, Wu Q, Chen HS, Lin H, Gao CY, Zhang LL, Xu ZQ, Zhang M, Zhou HD, Wang YJ (2017b) Comorbidity burden of dementia: a hospital-based retrospective study from 2003 to 2012 in seven cities in China. Neurosci Bull 33:703–710.  https://doi.org/10.1007/s12264-017-0193-3 CrossRefGoogle Scholar
  36. Weskamp G, Schlöndorff J, Lum L, Becherer JD, Kim TW, Saftig P, Hartmann D, Murphy G, Blobel CP (2004) Evidence for a critical role of the tumor necrosis factor alpha convertase (TACE) in ectodomain shedding of the p75 neurotrophin receptor (p75NTR). J Biol Chem 279:4241–4249.  https://doi.org/10.1074/jbc.M307974200 CrossRefGoogle Scholar
  37. Xin SH, Tan L, Cao X, Yu JT, Tan L (2018) Clearance of amyloid beta and tau in Alzheimer’s disease: from mechanisms to therapy. Neurotox Res 34:733–748.  https://doi.org/10.1007/s12640-018-9895-1 CrossRefGoogle Scholar
  38. Yaar M, Zhai S, Pilch PF, Doyle SM, Eisenhauer PB, Fine RE, Gilchrest BA (1997) Binding of beta-amyloid to the p75 neurotrophin receptor induces apoptosis. A possible mechanism for Alzheimer’s disease. J Clin Invest 100:2333–2340.  https://doi.org/10.1172/JCI119772 CrossRefGoogle Scholar
  39. Yaar M, Arble BL, Stewart KB, Qureshi NH, Kowall NW, Gilchrest BA (2008) p75NTR antagonistic cyclic peptide decreases the size of beta amyloid-induced brain inflammation. Cell Mol Neurobiol 28:1027–1031.  https://doi.org/10.1007/s10571-008-9298-6 CrossRefGoogle Scholar
  40. Yao XQ, Jiao SS, Saadipour K, Zeng F, Wang QH, Zhu C, Shen LL, Zeng GH, Liang CR, Wang J, Liu YH, Hou HY, Xu X, Su YP, Fan XT, Xiao HL, Lue LF, Zeng YQ, Giunta B, Zhong JH, Walker DG, Zhou HD, Tan J, Zhou XF, Wang YJ (2015) p75NTR ectodomain is a physiological neuroprotective molecule against amyloid-beta toxicity in the brain of Alzheimer’s disease. Mol Psychiatry 20:1301–1310.  https://doi.org/10.1038/mp.2015.49 CrossRefGoogle Scholar
  41. Yeo TT, Chua-Couzens J, Butcher LL, Bredesen DE, Cooper JD, Valletta JS, Mobley WC, Longo FM (1997) Absence of p75NTR causes increased basal forebrain cholinergic neuron size, choline acetyltransferase activity, and target innervation. J Neurosci 17:7594–7605CrossRefGoogle Scholar
  42. Zeng F, Lu JJ, Zhou XF, Wang YJ (2011) Roles of p75NTR in the pathogenesis of Alzheimer’s disease: a novel therapeutic target. Biochem Pharmacol 82:1500–1509.  https://doi.org/10.1016/j.bcp.2011.06.040 CrossRefGoogle Scholar
  43. Zhang W, Wang LZ, Yu JT, Chi ZF, Tan L (2012) Increased expressions of TLR2 and TLR4 on peripheral blood mononuclear cells from patients with Alzheimer’s disease. J Neurol Sci 315:67–71.  https://doi.org/10.1016/j.jns.2011.11.032 CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Yali Xu
    • 1
    • 2
  • Wei-Wei Li
    • 1
  • Jun Wang
    • 1
  • Chi Zhu
    • 1
  • Ying-Ying Shen
    • 1
  • An-Yu Shi
    • 1
  • Gui-Hua Zeng
    • 1
  • Zhi-Qiang Xu
    • 1
  • Xin-Fu Zhou
    • 3
  • Yan-Jiang Wang
    • 1
    Email author
  1. 1.Department of Neurology, Daping HospitalThird Military Medical UniversityChongqingChina
  2. 2.Department of Geriatrics, Chongqing General HospitalUniversity of Chinese Academy of SciencesChongqingChina
  3. 3.Division of Health Sciences, School of Pharmacy and Medical Sciences and Sansom InstituteUniversity of South AustraliaAdelaideAustralia

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