Altered expression of Notch1 in Alzheimer's disease

Autoři: Sun-Jung Cho aff001;  Sang-Moon Yun aff001;  Chulman Jo aff001;  Jihyun Jeong aff001;  Moon Ho Park aff002;  Changsu Han aff003;  Young Ho Koh aff001
Působiště autorů: Division of Brain Diseases, Center for Biomedical Sciences, Korea National Institute of Health, 187 Osongsaengmyeong2-ro, Osong-eup, Heungdeok-gu, Cheongju-si, Chungcheongbuk-do, Republic of Korea aff001;  Departments of Neurology, Korea University Medical College, Ansan Hospital, 123 Jeokgeum-ro, Danwon-gu, Ansan-si, Gyeonggi-do, Republic of Korea aff002;  Departments of Psychiatry, Korea University Medical College, Ansan Hospital, 123 Jeokgeum-ro, Danwon-gu, Ansan-si, Gyeonggi-do, Republic of Korea aff003
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0224941


Notch signaling is an evolutionarily conserved pathway that regulates cell-cell interactions through binding of Notch family receptors to their cognate ligands. Notch signaling has an essential role in vascular development and angiogenesis. Recent studies have reported that Notch may be implicated in Alzheimer’s disease (AD) pathophysiology. We measured the levels of soluble Notch1 (sNotch1) in the plasma samples from 72 dementia patients (average age 75.1 y), 89 subjects with amnestic mild cognitive impairment (MCI) (average age 73.72 y), and 150 cognitively normal controls (average age 72.34 y). Plasma levels of sNotch1 were 25.27% lower in dementia patients as compared to healthy control subjects. However, the level of Notch1 protein was significantly increased in human brain microvascular endothelial cells (HBMECs) after amyloid-beta treatment. Also, Notch1 mRNA level was significantly increased in HBMECs and iPSC-derived neuronal cells from AD patient compared to normal control. These results indicate that altered expression of Notch1 might be associated with the risk of Alzheimer’s disease.

Klíčová slova:

Alzheimer's disease – Angiogenesis – Cognitive impairment – Dementia – Endothelial cells – Gene expression – Neuronal differentiation – Notch signaling


1. Zhiyou BZ, Yanqing D, Shouqin S, Faming Z, Wenqing Z, Ziaoli L, et al. Notch signaling in cerebrovascular diseases. Molecular Medicine Reports. 2016;14(4):2883–3898. doi: 10.3892/mmr.2016.5641 27574001

2. Brou LF, Gupta N, Bessia C, LeBail O, Doedens JR, Cumano A,et al. A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE. Mol Cell. 2000;5(2):207–16. doi: 10.1016/s1097-2765(00)80417-7 10882063

3. De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, et al. A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature. 1999;398(6727):518–22. doi: 10.1038/19083 10206645

4. Alberi L, Hoey S, Brai E, Scotti AL, Marathe S. Notch signaling in the brain: In good and bad times. Ageing Research Reviews. 2013;12:801–14. doi: 10.1016/j.arr.2013.03.004 23570941

5. Shawber CJ, Kitajewski J. Notch function in the vasculature: insights from zebrafich, mouse and man. Bioessays. 2004;26:225–34. doi: 10.1002/bies.20004 14988924

6. Fortini C, Caliceti C, Aquila G, Morelli MB, Pavasini R, Rizzo P. The Role of the Notch Pathway in Atherosclerosis. Indian Journal of Cardio Biology & Clinical Sciences. 2014;1(1):103.

7. Geudens I, Gerhardt H. Coordinating cell behaviour during blood vessel formation. Development. 2011;138:4569–83. doi: 10.1242/dev.062323 21965610

8. Cho SJ, Park MH, Han C, Yoon K, Koh YH. VEGFR2 alteration in Alzheimer's disease. Scientific Reports. 2017;7:17713. doi: 10.1038/s41598-017-18042-1 29255164

9. Yoon KJ, Lee HR, Jo YS, An K., Jung SY, Jeong MW, et al. Mind bomb-1 is an essential modulator of long-term memory and synaptic plasticity via the Notch signaling pathway. Molecular Brain. 2012;5:40. doi: 10.1186/1756-6606-5-40 23111145

10. Lees GJ. The possible contribution of microglia and macrophages to delayed neuronal death after ischemia. Journal of Neurological science. 1993;114:119–22.

11. Basak O, Giachino C, Fiorini E, MacDonald HR, Taylor V. Neurogenic subventricular zone stem/progenitor cells are Notch1-dependent in their active but not quiescent state. Journal of Neurological science. 2012;32:5654–566.

12. Brai E, Alina RN, Alberi L. Notch1 hallmarks fibrillary depositions in sporadic Alzheimer's disease. Acta Neuropathology communications. 2016;4(1):64–84.

13. Wang YW, Ren HL, Wang HF, Li FD, Li HH, Zheng YH. Combining detection of Notch1 and tumor necrosis factor-1α converting enzyme is a reliable biomarker for the diagnosis of abdominal aortic aneurysms. Life Sciences. 2015;127:39–45. doi: 10.1016/j.lfs.2015.02.009 25744398

14. Han C, Jo SA, Kim NH, Jo I, Park MH. Study design and methods of the Ansan Geriatric Study (AGE study). BMC Neurol. 2009;9:10. Epub 2009/02/25. doi: 10.1186/1471-2377-9-10 19236723; PubMed Central PMCID: PMC2654857.

15. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. 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. 1984;34(7):939–44. doi: 10.1212/wnl.34.7.939 6610841.

16. Cho SJ, Lim HJ, Jo C, Park MH, Han C, Koh YH. Plasma ATG5 is increased in Alzheimer’s disease. Scientific Reports. 2019;9:4741. doi: 10.1038/s41598-019-41347-2 30894637

17. Lee JH, Lee KU, Lee DY, Kim KW, Jhoo JH, Kim JH, et al. Development of the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease Assessment Packet (CERAD-K): clinical and neuropsychological assessment batteries. J Gerontol B Psychol Sci Soc Sci. 2002;57(1):P47–53. doi: 10.1093/geronb/57.1.p47 11773223.

18. Association AP. Diagnostic and Statistical Manual of Mental Disorders. 4th edition ed. Washington: American Psychiatric Press; 1994.

19. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol. 1999;56(3):303–8. doi: 10.1001/archneur.56.3.303 10190820.

20. Jang BG, Yun SM, Ahn K, Song JH, Jo SA, Kim YY, et al. Plasma carbonic anhydrase II protein is elevated in Alzheimer's disease. J Alzheimers Dis. 2010;21(3):939–45. Epub 2010/07/17. doi: 10.3233/JAD-2010-100384 20634585.

21. Kim J, Park MH, Kim E, Han C, Jo SA, Jo I. Plasma homocysteine is associated with the risk of mild cognitive impairment in an elderly Korean population. J Nutr. 2007;137(9):2093–7. doi: 10.1093/jn/137.9.2093 17709448.

22. Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 1993;43(11):2412–4. Epub 1993/11/01. doi: 10.1212/wnl.43.11.2412-a 8232972.

23. Youn SW, Lee SW, Lee J, Jeong HK, Suh JW, Yoon CH, et al. COMP-Ang1 stimulates HIF-1alpha-mediated SDF-1 overexpression and recovers ischemic injury through BM-derived progenitor cell recruitment. Blood. 2011;117(16):4376–86. Epub 2011/01/05. doi: 10.1182/blood-2010-07-295964 21200018.

24. Whitehouse PJ, Sciulli CG, Mason RM. Dementia drug development: use of information systems to harmonize global drug development. Psychopharmacol Bull. 1997;33(1):129–33. 9133764

25. Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA. 1997;277(10):813–7. 9052711

26. Ramasamy SK, Kusumbe AP, Schiller M, Zeuschner D, Bixel MG, Milia C, et al. Blood flow controls bone vascular function and osteogenesis. Nature Communications. 2016;7:13601. doi: 10.1038/ncomms13601 27922003

27. Mack JJ, Iruela-Arispe ML. NOTCH regulation of the endothelial cell phenotype. Current Opinion in Hematology. 2018;25(3):212–8. doi: 10.1097/MOH.0000000000000425 29547401

28. Sainson RCA, Harris AL. Hypoxia-regulated differentiation: let's step it up a Notch. Trends in Molecular Medicine. 2006;12(4):141–3. doi: 10.1016/j.molmed.2006.02.001 16513423

29. Gustafsson MV, Zheng X, Pereira T, Gradin K, Jin S, Lundkvist J, et al. Hypoxia requires notch signaling to maintain the undifferentiated cell state. Developmental Cell. 2005;9(5):617–28. doi: 10.1016/j.devcel.2005.09.010 16256737

30. Taylor KL, Henderson AM, Hughes CC. Notch activation during endothelial cell network formation in vitro targets the basic HLH transcription factor HESR-1 and downregulates VEGFR-2/KDR expression. Microvasc Res. 2002;64(3):372–83. Epub 2002/11/28. doi: 10.1006/mvre.2002.2443 12453432.

31. Carmeliet P. Angiogenesis in health and disease. Nat Med. 2003;9(6):653–60. Epub 2003/06/05. doi: 10.1038/nm0603-653 12778163.

32. Ryu JK, Cho T, Choi HB, Wang YT, McLarnon JG. Microglial VEGF receptor response is an integral chemotactic component in Alzheimer's disease pathology. J Neurosci. 2009;29(1):3–13. Epub 2009/01/09. doi: 10.1523/JNEUROSCI.2888-08.2009 19129379.

33. Shawber CJ, Das I, Francisco E, Kitajewski J. Notch signaling in primary endothelial cells. Ann N Y Acad Sci. 2003;995:162–70. Epub 2003/06/20. doi: 10.1111/j.1749-6632.2003.tb03219.x 12814948.

34. Nagarsheth MH, Viehman A, Lippa SM, Lippa CF. Notch-1 immunoexpression is increased in Alzheimer's and Pick's disease. J Neurol Sci. 2006;244(1–2):111–6. Epub 2006/02/14. doi: 10.1016/j.jns.2006.01.007 16473372.

35. Fischer DF, van Dijk R, Sluijs JA, Nair SM, Racchi M, Levelt CN, et al. Activation of the Notch pathway in Down syndrome: cross-talk of Notch and APP. FASEB J. 2005;19(11):1451–8. Epub 2005/08/30. doi: 10.1096/ 16126912.

36. Yoon K, Nery S, Rutlin ML, Radtke F, Fishell G, Gaiano N. Fibroblast Growth Factor Receptor Signaling Promotes Radial Glial Identity and Interacts with Notch1 Signaling in Telencephalic Progenitors. Journal of Neuroscience. 2004;24(43):9497–506. doi: 10.1523/JNEUROSCI.0993-04.2004 15509736

37. Yoon K, Gaiano N. Notch signaling in the mammalian central nervous system: insights from mouse mutants. Nature Neuroscience. 2005;8:709–15. doi: 10.1038/nn1475 15917835

38. Wang MM. Notch signaling and Notch signaling modifiers. International Journal of Biochemistry and Cell Biology. 2011;43(11):1550–62. doi: 10.1016/j.biocel.2011.08.005 21854867

39. Wei Z, Chigurupati S, Arumugam TV, Jo DG, Li H, Chan SL. Notch activation enhances the microglia-mediated inflammatory response associated with focal cerebral ischemia. Stroke. 2011;42:2589–94. doi: 10.1161/STROKEAHA.111.614834 21737799

40. Mathieu P, Adami PVM, Morelli L. Notch signaling in the pathologic adult brain. Biomolecular Concepts. 2013;4(5):465–76. doi: 10.1515/bmc-2013-0006 25436753

41. Lockstone HE, Harris LW, Swatton JE, Wayland MT, Holland AJ, Bahn S. Gene expression profiling in the adult Down syndrome brain. Genomics. 2007;90(6):647–60. doi: 10.1016/j.ygeno.2007.08.005 17950572

42. Cuello AC, Hall H, Carmo SD. Experimental Pharmacology in Transgenic Rodent Models of Alzheimer’s Disease. Frontiers in Phamacology. 2019;10:189.

43. Pedrosa AR, Trindade A, Fernandes AC, Carvalho C, Gigante J, Tavares AT, et al. Endothelial Jagged1 antagonizes Dll4 regulation of endothelial branching and promotes vascular maturation downstream of Dll4/Notch1. Arterioscler Thromn Vasc Biol. 2015;35:1134–46.

44. Krishnasamy K, Limbourg A, Kapanadze T, Gamrekelashvili J, Beger C, Hager C, et al. Blood vessel control of macrophage maturation promotes arteriogenesis in ischemia. Nature comm. 2017;8:952.

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2019 Číslo 11