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Current Alzheimer Research

Editor-in-Chief

ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

Research Article

Alterations in the Expression of Amyloid Precursor Protein Cleaving Enzymes mRNA in Alzheimer Peripheral Blood

Author(s): Prapimpun Wongchitrat*, Nattaporn Pakpian, Kuntida Kitidee, Kamonrat Phopin, Pornpatr A. Dharmasaroja and Piyarat Govitrapong

Volume 16, Issue 1, 2019

Page: [29 - 38] Pages: 10

DOI: 10.2174/1567205015666181109103742

Price: $65

Abstract

Background: Alzheimer’s disease (AD) is the most common cause of dementia in elderly populations. Changes in the expression of the Amyloid Precursor Protein (APP)-cleaving enzymes directly affect the formation of Amyloid Beta (Aβ) plaques, a neuropathological hallmark of AD.

Objective: We used peripheral blood from AD patients to investigate the expression of genes related to APP-processing [(β-site APP-cleaving enzyme 1 (BACE1), presenilin1 (PSEN1), and a disintegrin and metalloproteinase family 10 (ADAM10) and 17 (ADAM17)] and the epigenetic genes sirtuin (SIRT)1-3, which regulate Aβ production.

Method: Real-time polymerase chain reactions were performed to determine the specific mRNA levels in plasma. The mRNA levels in AD patients were compared to those in healthy persons and assessed in relation to the subjects’ cognitive performance.

Results: BACE1 mRNA level in AD subjects was significantly higher than those of healthy controls, whereas ADAM10 level was significantly lower in the AD subjects. The SIRT1 level was significantly decreased, while that of SIRT2 was increased in AD subjects and elderly controls compared to levels in healthy young control. In addition, correlations were found between the expression levels of BACE1, ADAM10 and SIRT1 and cognitive performance scores. Total Aβ (Aβ40+Aβ42) levels and the Aβ40/Aβ42 ratio were significantly increased in the AD subjects, whereas decrease in plasma Aβ42 was found in AD subjects. There was a negative correlation between Aβ40 or total Aβ and Thai Mental State Examination (TMSE) while there was no correlation between Aβ40/Aβ42 ratio or Aβ42 and TMSE.

Conclusion: The present findings provide evidence and support for the potential roles of these enzymes that drive Aβ synthesis and for epigenetic regulation in AD progression and development, which can possibly be considered peripheral markers of AD.

Keywords: Alzheimer's disease, APP-cleaving enzymes, sirtuins, amyloid beta, plasma biomarkers, gene expression.

[1]
Finder VH. Alzheimer’s disease: a general introduction and pathomechanism. J Alzheimers Dis 22(3): 5-19. (2010).
[2]
Kalaria RN, Maestre GE, Arizaga R, Friedland RP, Galasko D, Hall K, et al. Alzheimer’s disease and vascular dementia in developing countries: prevalence, management, and risk factors. Lancet Neurol 7(9): 812-26. (2008).
[3]
Comas Herrera A, Prince M, Knapp M, Karagiannidou M, Guerchet M. World Alzheimer Report 2016: improving healthcare for people with dementia Coverage, quality and costs now and in the future. (2016).
[4]
Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global prevalence of dementia: a systematic review and metaanalysisAlzheimers Dement 9(1): 63-75 e2 (2013).
[5]
Sosa-Ortiz AL, Acosta-Castillo I, Prince MJ. Epidemiology of dementias and Alzheimer’s disease. Arch Med Res 43(8): 600-8. (2012).
[6]
O’Brien RJ, Wong PC. Amyloid precursor protein processing and Alzheimer’s disease. Annu Rev Neurosci 34: 185-204. (2011).
[7]
Jack CR Jr, Holtzman DM. Biomarker modeling of Alzheimer’s disease. Neuron 80(6): 1347-58. (2013).
[8]
Roberts KF, Elbert DL, Kasten TP, Patterson BW, Sigurdson WC, Connors RE, et al. Amyloid-beta efflux from the central nervous system into the plasma. Ann Neurol 76(6): 837-44. (2014).
[9]
Xiang Y, Bu XL, Liu YH, Zhu C, Shen LL, Jiao SS, et al. Physiological amyloid-beta clearance in the periphery and its therapeutic potential for Alzheimer’s disease. Acta Neuropathol 130(4): 487-99. (2015).
[10]
Zhang YW, Thompson R, Zhang H, Xu H. APP processing in Alzheimer’s disease. Mol Brain 4: 3. (2011).
[11]
Cai H, Wang Y, McCarthy D, Wen H, Borchelt DR, Price DL, et al. BACE1 is the major beta-secretase for generation of Abeta peptides by neurons. Nat Neurosci 4(3): 233-4. (2001).
[12]
Suh J, Choi SH, Romano DM, Gannon MA, Lesinski AN, Kim DY, et al. ADAM10 missense mutations potentiate beta-amyloid accumulation by impairing prodomain chaperone function. Neuron 80(2): 385-401. (2013).
[13]
Julien C, Tremblay C, Emond V, Lebbadi M, Salem N Jr, Bennett DA, et al. Sirtuin 1 reduction parallels the accumulation of tau in Alzheimer disease. J Neuropathol Exp Neurol 68(1): 48-58. (2009).
[14]
Jesko H, Wencel P, Strosznajder RP, Strosznajder JB. Sirtuins and their roles in brain aging and neurodegenerative disorders. Neurochem Res 42(3): 876-90. (2017).
[15]
Donmez G, Wang D, Cohen DE, Guarente L. SIRT1 suppresses beta-amyloid production by activating the alpha-secretase gene ADAM10. Cell 142(2): 320-32. (2010).
[16]
Qin W, Yang T, Ho L, Zhao Z, Wang J, Chen L, et al. Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction. J Biol Chem 281(31): 21745-54. (2006).
[17]
Lutz MI, Milenkovic I, Regelsberger G, Kovacs GG. Distinct patterns of sirtuin expression during progression of Alzheimer’s disease. Neuromolecular Med 16(2): 405-14. (2014).
[18]
Weir HJ, Murray TK, Kehoe PG, Love S, Verdin EM, O’Neill MJ, et al. CNS SIRT3 expression is altered by reactive oxygen species and in Alzheimer’s disease. PLoS One 7(11): e48225. (2012).
[19]
Train The Brain Forum Committee Thai Mental State Examination (TMSE). Siriraj Med J 45(6): 16. (1993).
[20]
Marwarha G, Raza S, Meiers C, Ghribi O. Leptin attenuates BACE1 expression and amyloid-beta genesis via the activation of SIRT1 signaling pathway. Biochim Biophys Acta 1842(9): 1587-95. (2014).
[21]
Guo P, Wang D, Wang X, Feng H, Tang Y, Sun R, et al. Effect and mechanism of fuzhisan and donepezil on the sirtuin 1 pathway and amyloid precursor protein metabolism in PC12 cells. Mol Med Rep 13(4): 3539-46. (2016).
[22]
Janelidze S, Stomrud E, Palmqvist S, Zetterberg H, van Westen D, Jeromin A, et al. Plasma beta-amyloid in Alzheimer’s disease and vascular disease. Sci Rep 6: 26801. (2016).
[23]
Nakamura A, Kaneko N, Villemagne VL, Kato T, Doecke J, Doré V, et al. High performance plasma amyloid-β biomarkers for Alzheimer’s disease. Nature 554: 249. (2018).
[24]
Giedraitis V, Sundelof J, Irizarry MC, Garevik N, Hyman BT, Wahlund LO, et al. The normal equilibrium between CSF and plasma amyloid beta levels is disrupted in Alzheimer’s disease. Neurosci Lett 427(3): 127-31. (2007).
[25]
Le Bastard N, Aerts L, Leurs J, Blomme W, De Deyn PP, Engelborghs S. No correlation between time-linked plasma and CSF Abeta levels. Neurochem Int 55(8): 820-5. (2009).
[26]
Rembach A, Faux NG, Watt AD, Pertile KK, Rumble RL, Trounson BO, et al. Changes in plasma amyloid beta in a longitudinal study of aging and Alzheimer’s disease. Alzheimers Dement 10(1): 53-61. (2014).
[27]
Tamaoka A, Fukushima T, Sawamura N, Ishikawa K, Oguni E, Komatsuzaki Y, et al. Amyloid beta protein in plasma from patients with sporadic Alzheimer’s disease. J Neurol Sci 141(1-2): 65-8. (1996).
[28]
Gabelle A, Richard F, Gutierrez L-A, Schraen S, Delva F, Rouaud O, et al. Plasma amyloid-β levels and prognosis in incident dementia cases of the 3-City Study. J Alzheimers Dis 33(2): 381-91. (2013).
[29]
Fei M, Jianghua W, Rujuan M, Wei Z, Qian W. The relationship of plasma Abeta levels to dementia in aging individuals with mild cognitive impairment. J Neurol Sci 305(1-2): 92-6. (2011).
[30]
Zhou L, Chan KH, Chu LW, Kwan JS, Song YQ, Chen LH, et al. Plasma amyloid-beta oligomers level is a biomarker for Alzheimer’s disease diagnosis. Biochem Biophys Res Commun 423(4): 697-702. (2012).
[31]
Luo Y, Bolon B, Damore MA, Fitzpatrick D, Liu H, Zhang J, et al. BACE1 (beta-secretase) knockout mice do not acquire compensatory gene expression changes or develop neural lesions over time. Neurobiol Dis 14(1): 81-8. (2003).
[32]
Cheng X, He P, Lee T, Yao H, Li R, Shen Y. High activities of BACE1 in brains with mild cognitive impairment. Am J Pathol 184(1): 141-7. (2014).
[33]
Mukda S, Panmanee J, Boontem P, Govitrapong P. Melatonin administration reverses the alteration of amyloid precursor protein-cleaving secretases expression in aged mouse hippocampus. Neurosci Lett 621: 39-46. (2016).
[34]
Lu H, Zhu XC, Jiang T, Yu JT, Tan L. Body fluid biomarkers in Alzheimer’s disease. Ann Transl Med 3(5): 70. (2015).
[35]
Shen Y, Wang H, Sun Q, Yao H, Keegan AP, Mullan M, et al. Increased plasma beta-secretase 1 may predict conversion to Alzheimer’s disease dementia in individuals with mild cognitive impairment. Biol Psychiatry 83(5): 447-55. (2018).
[36]
Gertsik N, Chau DM, Li YM. γ-Secretase inhibitors and modulators induce distinct conformational changes in the active sites of gamma-secretase and signal peptide peptidase. ACS Chem Biol 10(8): 1925-31. (2015).
[37]
Tanzi RE. The genetics of Alzheimer disease. Cold Spring Harb Perspect Med 2(10) (2012).
[38]
Thordardottir S, Graff C. Findings from the Swedish Study on Familial Alzheimer’s disease including the APP swedish double mutation. J Alzheimers Dis 64(s1): S491-96. (2018).
[39]
Isoe-Wada K, Urakami K, Wakutani Y, Adachi Y, Arai H, Sasaki H, et al. Alteration in brain presenilin-1 mRNA expression in sporadic Alzheimer’s disease. Eur J Neurol 6(2): 163-7. (1999).
[40]
Delvaux E, Bentley K, Stubbs V, Sabbagh M, Coleman PD. Differential processing of amyloid precursor protein in brain and in peripheral blood leukocytes. Neurobiol Aging 34(6): 1680-6. (2013).
[41]
Carboni L, Lattanzio F, Candeletti S, Porcellini E, Raschi E, Licastro F, et al. Peripheral leukocyte expression of the potential biomarker proteins Bdnf, Sirt1, and Psen1 is not regulated by promoter methylation in Alzheimer’s disease patients. Neurosci Lett 605: 44-8. (2015).
[42]
Saftig P, Lichtenthaler SF. The alpha secretase ADAM10: a metalloprotease with multiple functions in the brain. Prog Neurobiol 135: 1-20. (2015).
[43]
Ohno M, Hiraoka Y, Lichtenthaler SF, Nishi K, Saijo S, Matsuoka T, et al. Nardilysin prevents amyloid plaque formation by enhancing alpha-secretase activity in an Alzheimer’s disease mouse model. Neurobiol Aging 35(1): 213-22. (2014).
[44]
Bernstein HG, Bukowska A, Krell D, Bogerts B, Ansorge S, Lendeckel U. Comparative localization of ADAMs 10 and 15 in human cerebral cortex normal aging, Alzheimer disease and Down syndrome. J Neurocytol 32(2): 153-60. (2003).
[45]
Colciaghi F, Borroni B, Pastorino L, Marcello E, Zimmermann M, Cattabeni F, et al. α-Secretase ADAM10 as well as αAPPs is reduced in platelets and CSF of Alzheimer disease patients. Mol Med 8(2): 67-74. (2002).
[46]
Postina R, Schroeder A, Dewachter I, Bohl J, Schmitt U, Kojro E, et al. A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. J Clin Invest 113(10): 1456-64. (2004).
[47]
Schmitt U, Hiemke C, Fahrenholz F, Schroeder A. Over-expression of two different forms of the alpha-secretase ADAM10 affects learning and memory in mice. Behav Brain Res 175(2): 278-84. (2006).
[48]
Manzine PR, Barham EJ, Vale Fde A, Selistre-de-Araujo HS, Iost Pavarini SC, Cominetti MR. Correlation between mini-mental state examination and platelet ADAM10 expression in Alzheimer’s disease. J Alzheimers Dis 36(2): 253-60. (2013).
[49]
Manzine PR, de Franca Bram JM, Barham EJ, do Vale Fde A, Selistre-de-Araujo HS, Cominetti MR, et al. ADAM10 as a biomarker for Alzheimer’s disease: a study with Brazilian elderly. Dement Geriatr Cogn Disord 35(1-2): 58-66. (2013).
[50]
Manzine PR, Barham EJ, Vale FA, Selistre-de-Araujo HS, Pavarini SC, Cominetti MR. Platelet a disintegrin and metallopeptidase 10 expression correlates with clock drawing test scores in Alzheimer’s disease. Int J Geriatr Psychiatry 29(4): 414-20. (2014).
[51]
Tang K, Hynan LS, Baskin F, Rosenberg RN. Platelet amyloid precursor protein processing: a bio-marker for Alzheimer’s disease. J Neurol Sci 240(1-2): 53-8. (2006).
[52]
Schuck F, Wolf D, Fellgiebel A, Endres K. Increase of alpha-Secretase ADAM10 in platelets along cognitively healthy aging. J Alzheimers Dis 50(3): 817-26. (2016).
[53]
Allinson TM, Parkin ET, Turner AJ, Hooper NM. ADAMs family members as amyloid precursor protein alpha-secretases. J Neurosci Res 74(3): 342-52. (2003).
[54]
Sun Q, Hampel H, Blennow K, Lista S, Levey A, Tang B, et al. Increased plasma TACE activity in subjects with mild cognitive impairment and patients with Alzheimer’s disease. J Alzheimers Dis 41(3): 877-86. (2014).
[55]
Jenwitheesuk A, Boontem P, Wongchitrat P, Tocharus J, Mukda S, Govitrapong P. Melatonin regulates the aging mouse hippocampal homeostasis via the sirtuin1-FOXO1 pathway. EXCLI J 16: 340-53. (2017).
[56]
Owczarz M, Budzinska M, Domaszewska-Szostek A, Borkowska J, Polosak J, Gewartowska M, et al. miR-34a and miR-9 are overexpressed and SIRT genes are downregulated in peripheral blood mononuclear cells of aging humans. Exp Biol Med (Maywood) 242(14): 1453-61. (2017).
[57]
Kumar R, Chaterjee P, Sharma PK, Singh AK, Gupta A, Gill K, et al. Sirtuin1: a promising serum protein marker for early detection of Alzheimer’s disease. PLoS One 8(4): e61560. (2013).
[58]
Silva DF, Esteves AR, Oliveira CR, Cardoso SM. Mitochondrial metabolism power SIRT2-dependent deficient traffic causing Alzheimer’s-disease related pathology. Mol Neurobiol 54(6): 4021-40. (2017).
[59]
Luthi-Carter R, Taylor DM, Pallos J, Lambert E, Amore A, Parker A, et al. SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis. Proc Natl Acad Sci USA 107(17): 7927-32. (2010).
[60]
Guan Q, Wang M, Chen H, Yang L, Yan Z, Wang X. Aging-related 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurochemial and behavioral deficits and redox dysfunction: improvement by AK-7. Exp Gerontol 82: 19-29. (2016).
[61]
Biella G, Fusco F, Nardo E, Bernocchi O, Colombo A, Lichtenthaler SF, et al. Sirtuin 2 inhibition improves cognitive performance and acts on amyloid-beta protein precursor processing in two Alzheimer’s disease mouse models. J Alzheimers Dis 53(3): 1193-207. (2016).
[62]
Yin J, Han P, Song M, Nielsen M, Beach TG, Serrano GE, et al. Amyloid-beta increases tau by mediating sirtuin 3 in Alzheimer’s disease. Mol Neurobiol (2018).
[63]
Hirschey MD, Shimazu T, Goetzman E, Jing E, Schwer B, Lombard DB, et al. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 464(7285): 121-5. (2010).
[64]
Han C, Someya S. Maintaining good hearing: calorie restriction, Sirt3, and glutathione. Exp Gerontol 48(10): 1091-5. (2013).
[65]
Rice CM, Sun M, Kemp K, Gray E, Wilkins A, Scolding NJ. Mitochondrial sirtuins--a new therapeutic target for repair and protection in multiple sclerosis. Eur J Neurosci 35(12): 1887-93. (2012).
[66]
Panmanee J, Nopparat C, Chavanich N, Shukla M, Mukda S, Song W, et al. Melatonin regulates the transcription of βAPP-cleaving secretases mediated through melatonin receptors in human neuroblastoma SH-SY5Y cells. J Pineal Res 59(3): 308-20. (2015).
[67]
Xu J, Yun X, Jiang J, Wei Y, Wu Y, Zhang W, et al. Hepatitis B virus X protein blunts senescence-like growth arrest of human hepatocellular carcinoma by reducing Notch1 cleavage. Hepatology 52(1): 142-54. (2010).
[68]
Durand D, Carniglia L, Beauquis J, Caruso C, Saravia F, Lasaga M. Astroglial mGlu3 receptors promote alpha-secretase-mediated amyloid precursor protein cleavage. Neuropharmacology 79: 180-9. (2014).
[69]
Manzine PR, Marcello E, Borroni B, Kamphuis W, Hol E, Padovani A, et al. ADAM10 gene expression in the blood cells of Alzheimer’s disease patients and mild cognitive impairment subjects. Biomarkers 20(3): 196-201. (2015).
[70]
Abe N, Uchida S, Otsuki K, Hobara T, Yamagata H, Higuchi F, et al. Altered sirtuin deacetylase gene expression in patients with a mood disorder. J Psychiatr Res 45(8): 1106-12. (2011).
[71]
Yang J, Bielenberg DR, Rodig SJ, Doiron R, Clifton MC, Kung AL, et al. Lipocalin 2 promotes breast cancer progression. Proc Natl Acad Sci USA 106(10): 3913-8. (2009).

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