BLMH and APOE genes in Alzheimer Disease: A possible relation


Alzheimer disease (AD) is a progressive and irreversible neurodegenerative disorder that is characterized by cognitive decline, memory loss and confusion. The E4 allele of the apolipoprotein E gene (APOE) is associated with AD and it is the main genetic risk factor for disease. Although the exact physiological function is unknown, bleomycin hydrolase (BLMH) may also be associated with AD development, although previous immunohistochemical findings havebeen inconsistent. Therefore, the purpose ofthis study was to evaluate the genotypic and allele frequencies of theAPOEgene andBLMH1450 G> A polymorphism and assessBLMHexpression using PCR-RFLP and RT-qPCR analyses ofblood samples from patients with Alzheimer disease (AD), healthy elderly adults (EC) andhealthyyoung subjects(YC). BLMHexpression wassignificantly different among groups (p= 0.015) and there was substantial reduction with age and with AD. TheAPOEandBLMHgenotype frequency did not diverge from the Hardy-Weinberg equilibrium. There was a higher frequency of genotype 3/3 inall subjects (61.1%) and the AD group demonstrated a higher frequency of allele 4; however, differences ingenotype and allele distributions were statistically different among groups.

Share and Cite:

Ximenez, J. , Rasmussen, L. , Orcini, W. , Labio, R. , Arruda, G. , Bertolucci, P. , Smith, M. and Payão, S. (2013) BLMH and APOE genes in Alzheimer Disease: A possible relation. Advances in Alzheimer's Disease, 2, 117-121. doi: 10.4236/aad.2013.23015.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Burns, A. and Iliffe, S. (2009) Alzheimer’s disease. BMJ, 338, b158. doi:1 0.1136/bmj.b158
[2] Mayeux, R. and Stern, Y. (2012) Epidemiology of Alzheimer disease. Nature Reviews Neurology, 7, 137-152.
[3] Gandy, S. (2005) The role of cerebral amyloid beta accumulation in common forms of Alzheimer disease. Journal of Clinical Investigation, 115, 1121-1129.
[4] Nelson, P.T., Head, E., Schmitt, F.A., Davis, P.R., Neltner, J.H., Jicha, G.A., et al. (2011) Alzheimer’s disease is not “brain aging”: Neuropathological, genetic, and epidemiological human studies. Acta Neuropathologica, 21, 571-587. doi:10.1007/s00401-011-0826-y
[5] Kaden, D., Munter, L.M., Reif, B. and Multhaup, G. (2012) The amyloid precursor protein and its homologues: structural and functional aspects of native and pathogenic oligomerization. European Journal of Cell Biology, 91, 234-239. doi:10.1016/j.ejcb.2011.01.017
[6] Bu, G. (2009) Apolipoprotein E and its receptors in Alzheimer’s disease: Pathways, pathogenesis and therapy. Nature Reviews Neuroscience, 10, 333-344. doi:10.1038/nrn2620
[7] Abasolo, N., Torrell, H., Roig, B., Moyano, S., Vilella, E. and Martorell, L. (2011) RT-qPCR study on postmortem brain samples from patients with major psychiatric disorders: Reference genes and specimen characteristics. Journal of Psychiatric Research, 45, 1411-1418. doi:10.1016/j.jpsychires.2011.06.001
[8] Hu, C.J., Sung, S.M., Liu, H.C., Hsu, W.C., Lee, L.S., Lee, C.C., Tsai, C.H. and Chang, J.G. (2000) Genetic risk factors of sporadic Alzheimer’s disease among Chinese in Taiwan. The Journal of Neuroscience, 181, 127-131. doi:10.1016/S0022-510X(00)00443-3
[9] Haas, E.C., Zwart, N., Meijer, C., Nuver, J., Boezen, H.M., Suurmeijer, A.J., Hoekstra, H.J., van der Steege, G., Sleijfer, D.T. and Gietema, J.A. (2008) Variation in bleomycin hydrolase gene is associated with reduced survival after chemotherapy for testicular germ cell cancer. Journal of Clinical Oncology, 26, 470-476
[10] Namba, Y., Ouchi, Y., Takeda, A., Ueki, A. and Ikeda K. (1999) Bleomycin hydrolase immunoreactivity in senile plaque in the brains of patients with Alzheimer’s disease. Brain Research, 830, 200-202. doi:10.1016/S0006-8993(99)01435-3
[11] Malherbe, P., Faull, R.L. and Richards, J.G. (2000) Re- gional and cellular distribution of bleomycin hydrolase mRNA in human brain: comparison between Alzheimer’s diseased and control brains. Neuroscience Letters, 3, 281, 37-40.
[12] Kajiya, A., Kaji, H., Isobe, T. and Takeda, A. (2006) Processing of amyloid beta-peptides by neutral cysteine protease bleomycin hydrolase. Protein & Peptide Letters, 13, 119-123. doi:10.2174/092986606775101562
[13] Katz, S., Ford, A.B., Moskowitz, R.W., Jackson, B.A. and Jaffe, M.W. (1963) Studies of Illness in the Aged. The Index of Adl: A Standardized Measure of Biological and Psychosocial Function. Jama, 185, 914-919. doi:10.1001/jama.1963.03060120024016
[14] Bertolucci, P.H., Okamoto, I.H., Brucki, S.M., Siviero, M.O., Toniolo, J. and Ramos, L.R. (2001) Applicability of the CERAD neuropsychological battery to Brazilian elderly. Arquivos de Neuro-Psiquiatria, 59, 532-536. doi:10.1590/S0004-282X2001000400009
[15] Mckhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D. and Stadlan, E.M. (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, 939-944. doi:10.1212/WNL.34.7.939
[16] Hixson, J.E. and Vernier, D.T. (1990) Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with Hhai. The Journal of Lipid Research, 31, 545-548.
[17] Tuimala, J., Szekely, G., Gundy, S., Hirvonen, A. and Norppa, H. (2002) Genetic polymorphisms of DNA repair and xenobiotic-metabolizing enzymes: Role in mutagen sensitivity. Carcinogenesis, 23, 1003-1008. doi:10.1093/carcin/23.6.1003
[18] Llorca, J., Rodríguez-Rodríguez, E., Dierssen-Sotos, T., Delgado-Rodríguez, M., Berciano, J. and Combarros, O. (2008) Meta-analysis of genetic variability in the bamyloid production, aggregation and degradation me- tabolic pathways and the risk of Alzheimer’s disease. Acta Neurologica Scandinavica, 117, 1-14.
[19] Altés, A., Paré, L., Esquirol, A., Xicoy, B., Rámila, E., Vicente, L., López, R., Orriols, J., Vall-Llovera, F., Sánchez-González, B., Del Río, E., Sureda, A., Páez, D. and Baiget, M. (2013) Pharmacogenetic analysis in the treatment of Hodgkin lymphoma. Leukemia & Lymphoma, 54, 1706-1712. doi:10.3109/10428194.2012.752080
[20] Lefterov, I.M., Kol-damova, R.P., Lefterova, M.I., Schwartz, D.R. and Lazo, J.S. (2001) Cysteine 73 in bleomycin hydrolase is critical for amyloid precursor protein processing. Biochemical and Biophysical Research Communications, 283, 994-999.
[21] Chen, J. and Stubbe, J. (2005) Bleomycins: towards better therapeutics. Nature Reviews Cancer, 5, 102-112. doi:10.1038/nrc1547
[22] Lefterov, I.M., Koldamova, R.P. and Lazo, J.S. (2000) Human bleomycin hydrolase regulates the secretion of amyloid precursor protein. The FASEB Journal, 14, 1837-1847. doi:10.1096/fj.99-0938com
[23] Montoya, S.E., Aston, C.E., DeKosky, S.T., Kamboh, M.I., Lazo, J.S. and Ferrell, R.E. (1998) Bleomycin hydrolase is associated with risk of sporadic Alzheimers disease. Nature Genetics, 18, 211-212. doi:10.1038/ng0398-211
[24] Farrer, L.A., Abraham, C.R., Haines, J.L., et al. (1998) Association between bleomycin hydrolase and Alzheimer’s disease in Caucasians. Annals of Neurology, 44, 808-811. doi:10.1002/ana.410440515
[25] Papassotiropoulos, A., Bagli, M., Jessen, F., Frahnert, C., Rao, M.L., Maier, W. and Heun R. (2000) Confirmation of the association between bleomycin hydrolase genotype and Alzheimer’s disease. Molecular Psychiatry, 5, 213-215. doi:10.1038/
[26] Thome, J., Gewirtz, J.C., Sakai, N., Zachariou, V., Retz-Junginger, P., Retz, W., Duman, R.S. and R?sler, M. (1999) Polymorphisms of the human apolipoprotein E promoter and bleomycin hydrolase gene: Risk factors for Alzheimer’s dementia? Neuroscience Letters, 274, 37-40. doi:10.1016/S0304-3940(99)00662-X
[27] Prince, J.A., Feuk, L., Sawyer, S.L., Gottfries, J., Ricksten, A., N?gga, K., Bog-danovic, N., Blennow, K. and Brookes, A.J. (2001) Lack of replication of association findings in complex disease: An analysis of 15 polymorphims in prior candidate genes for sporadic Alzheimer disease. European Journal of Human Genetics, 9, 437-444. doi:10.1038/sj.ejhg.5200651
[28] Smach, M.A., Charfeddine, B., Lammouchi, T., Othman, L.B., Letaief, A., Nafati, S., Dridi, H., Bennamou, S. and Limem, K. (2010) Analysis of association between bleomycin hydrolase and apolipoprotein E polymorphism in Alzheimer’s disease. Neurological Sciences, 31, 687-691. doi:10.1007/s10072-010-0234-4

Copyright © 2024 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.