Metabolic Brain Disease

, Volume 33, Issue 3, pp 933–937 | Cite as

A gender dimorphism in up-regulation of BACE1 gene expression in schizophrenia

  • Nafiseh Nafisi-Far
  • Soudeh Ghafouri-Fard
  • Akram Sadat Tabatabaei Panah
  • Arezou Sayad
  • Mohammad Taheri
Original Article


Schizophrenia has long been considered as a devastating brain disorder in which both genetic and environmental factors are involved. The BACE1 gene is one of the most important susceptibility genes for this disorder. However, the changes in BACE1 expression in schizophrenic patients compared with healthy subjects have not been evaluated yet. In this case-control study, we examined BACE1 expression in a group of 50 patients with schizophrenia and 50 healthy controls. The level of BACE1 gene expression was measured using Real-Time PCR. Substantial increase in gene expression was detected in the patients compared with normal individuals (P = 0.001). Furthermore, a gender dimorphism was observed in BACE1 gene expression in the patients in a way that the male patients manifested a statistically significant higher levels of BACE1 expression (P = 0.002). BACE1 might be implicated in the pathogenesis of schizophrenia. Besides, BACE1 physiology may be gender -based at some levels. Our findings warrant an investigation of BACE1 gene in a larger number of cases and controls.


BACE1 Schizophrenia Gender Dimorphism 



This study was supported by (grant number 12666) Shahid Beheshti University of Medical sciences.

Compliance with ethical standards

Conflicts of interest

The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.


  1. Barakat A, Dean B, Scarr E, Evin G (2010) Decreased Neuregulin 1 C-terminal fragment in Brodmann's area 6 of patients with schizophrenia. Schizophr Res 124(1–3):200–207CrossRefPubMedGoogle Scholar
  2. Devi L, Alldred MJ, Ginsberg SD, Ohno M (2010) Sex- and brain region-specific acceleration of beta-amyloidogenesis following behavioral stress in a mouse model of Alzheimer's disease. Molecular Brain 3:34CrossRefPubMedPubMedCentralGoogle Scholar
  3. Hu X, Fan Q, Hou H, Yan R (2016) Neurological dysfunctions associated with altered BACE1-dependent Neuregulin-1 signaling. J Neurochem 136(2):234–249CrossRefPubMedGoogle Scholar
  4. Hussain I, Powell D, Howlett DR, Tew DG, Meek TD, Chapman C, Gloger IS, Murphy KE, Southan CD, Ryan DM, Smith TS, Simmons DL, Walsh FS, Dingwall C, Christie G (1999) Identification of a novel aspartic protease (asp 2) as beta-secretase. Mol Cell Neurosci 14(6):419–427CrossRefPubMedGoogle Scholar
  5. Jiang S, Wang Y, Ma Q, Zhou A, Zhang X, Zhang YW (2012) M1 muscarinic acetylcholine receptor interacts with BACE1 and regulates its proteosomal degradation. Neurosci Lett 515(2):125–130CrossRefPubMedGoogle Scholar
  6. Kandalepas PC, Vassar R (2014) The normal and pathologic roles of the Alzheimer's beta-secretase, BACE1. Curr Alzheimer Res 11(5):441–449CrossRefPubMedPubMedCentralGoogle Scholar
  7. Lahiri DK, Ge YW, Rogers JT, Sambamurti K, Greig NH, Maloney B (2006) Taking down the unindicted co-conspirators of amyloid beta-peptide-mediated neuronal death: shared gene regulation of BACE1 and APP genes interacting with CREB, Fe65 and YY1 transcription factors. Curr Alzheimer Res 3(5):475–483CrossRefPubMedGoogle Scholar
  8. Law AJ, Lipska BK, Weickert CS, Hyde TM, Straub RE, Hashimoto R, Harrison PJ, Kleinman JE, Weinberger DR (2006) Neuregulin 1 transcripts are differentially expressed in schizophrenia and regulated by 5' SNPs associated with the disease. Proc Natl Acad Sci U S A 103(17):6747–6752CrossRefPubMedPubMedCentralGoogle Scholar
  9. Law AJ, Wang Y, Sei Y, O'Donnell P, Piantadosi P, Papaleo F et al (2012) Neuregulin 1-ErbB4-PI3K signaling in schizophrenia and phosphoinositide 3-kinase-p110delta inhibition as a potential therapeutic strategy. Proc Natl Acad Sci U S A 109(30):12165–12170CrossRefPubMedPubMedCentralGoogle Scholar
  10. Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J (2000) Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc Natl Acad Sci U S A 97(4):1456–1460CrossRefPubMedPubMedCentralGoogle Scholar
  11. Liu X, Bates R, Yin DM, Shen C, Wang F (2011) Su N, et al. specific regulation of NRG1 isoform expression by neuronal activity. J Neurosci Off J Soc Neurosci 31(23):8491–8501CrossRefGoogle Scholar
  12. Luo X, He W, Hu X, Yan R (2014) Reversible overexpression of bace1-cleaved neuregulin-1 N-terminal fragment induces schizophrenia-like phenotypes in mice. Biol Psychiatry 76(2):120–127CrossRefPubMedGoogle Scholar
  13. Marballi K, Cruz D, Thompson P, Walss-Bass C (2012) Differential neuregulin 1 cleavage in the prefrontal cortex and hippocampus in schizophrenia and bipolar disorder: preliminary findings. PLoS One 7(5):e36431CrossRefPubMedPubMedCentralGoogle Scholar
  14. Savonenko AV, Melnikova T, Laird FM, Stewart KA, Price DL, Wong PC (2008) Alteration of BACE1-dependent NRG1/ErbB4 signaling and schizophrenia-like phenotypes in BACE1-null mice. Proc Natl Acad Sci U S A 105(14):5585–5590CrossRefPubMedPubMedCentralGoogle Scholar
  15. Scarr E, Gibbons AS, Neo J, Udawela M, Dean B (2013) Cholinergic connectivity: it's implications for psychiatric disorders. Front Cell Neurosci 7:55CrossRefPubMedPubMedCentralGoogle Scholar
  16. Seshadri S, Kamiya A, Yokota Y, Prikulis I, Kano S, Hayashi-Takagi A, Stanco A, Eom TY, Rao S, Ishizuka K, Wong P, Korth C, Anton ES, Sawa A (2010) Disrupted-in-Schizophrenia-1 expression is regulated by beta-site amyloid precursor protein cleaving enzyme-1-neuregulin cascade. Proc Natl Acad Sci U S A 107(12):5622–5627CrossRefPubMedPubMedCentralGoogle Scholar
  17. Sinha S, Anderson JP, Barbour R, Basi GS, Caccavello R, Davis D, Doan M, Dovey HF, Frigon N, Hong J, Jacobson-Croak K, Jewett N, Keim P, Knops J, Lieberburg I, Power M, Tan H, Tatsuno G, Tung J, Schenk D, Seubert P, Suomensaari SM, Wang S, Walker D, Zhao J, McConlogue L, John V (1999) Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature 402(6761):537–540CrossRefPubMedGoogle Scholar
  18. 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 (New York, NY) 286(5440):735–741CrossRefGoogle Scholar
  19. Wang H, Li R, Shen Y (2013) Beta-secretase: its biology as a therapeutic target in diseases. Trends Pharmacol Sci 34(4):215–225CrossRefPubMedPubMedCentralGoogle Scholar
  20. Yan R, Bienkowski MJ, Shuck ME, Miao H, Tory MC, Pauley AM, Brashler JR, Stratman NC, Mathews WR, Buhl AE, Carter DB, Tomasselli AG, Parodi LA, Heinrikson RL, Gurney ME (1999) Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity. Nature 402(6761):533–537CrossRefPubMedGoogle Scholar
  21. Yang GJ, Murray JD, Repovs G, Cole MW, Savic A, Glasser MF, Pittenger C, Krystal JH, Wang XJ, Pearlson GD, Glahn DC, Anticevic A (2014) Altered global brain signal in schizophrenia. Proc Natl Acad Sci U S A 111(20):7438–7443CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Young Researchers and Elite Club, East Tehran BranchIslamic Azad UniversityTehranIran
  2. 2.Department of Biology, East Tehran BranchIslamic Azad UniversityTehranIran
  3. 3.Department of Medical GeneticsShahid Beheshti University of Medical sciencesTehranIran
  4. 4.Urogenital Stem Cell Research CenterShahid Beheshti University of Medical SciencesTehranIran

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