Alterations of aqueous humor Aβ levels in Aβ-infused and transgenic mouse models of Alzheimer disease

Autoři: Da Eun Kwak aff001;  Taeho Ko aff001;  Han Seok Koh aff004;  Yong Woo Ji aff004;  Jisu Shin aff001;  Kyeonghwan Kim aff001;  Hye Yun Kim aff001;  Hyung-Keun Lee aff004;  YoungSoo Kim aff001
Působiště autorů: Department of Pharmacy, Yonsei University, Incheon, Republic of Korea aff001;  Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea aff002;  Industrial Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea aff003;  Department of Ophthalmology, Institute of Vision Research, Yonsei University College of Medicine, Seoul, Republic of Korea aff004;  Department of Ophthalmology, National Health Insurance Service Ilsan Hospital, Goyang, Republic of Korea aff005;  Integrated Science and Engineering Division, Yonsei University, Incheon, Republic of Korea aff006
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: 10.1371/journal.pone.0227618


Alzheimer’s disease (AD) is an ageing-related neurodegenerative disease characterized and diagnosed by deposition of insoluble amyloid-β (Aβ) plaques in the brain. The plaque accumulation in the brain directly affects reduced levels of Aβ in cerebrospinal fluid (CSF) and blood, as Aβ can freely transport the blood-brain barrier, and clinical investigations have suggested these two biofluids as promising samples for in vitro diagnosis. Given that the human eye structurally resembles the brain and Aβ accumulation often observed in the ocular region of AD patients, in this study, we examined aqueous humor Aβ as another possible surrogate biomarker. First, using the acute Aβ-infused AD mouse model by injecting Aβ to the CSF in intracerebroventricular region of normal ICR mice, we investigated whether Aβ concentration in the aqueous humor in AD models is positively correlated with the concentration in the CSF. Then, we examined the correlation of aqueous humor Aβ levels with increased plaque deposition in the brain and reduced Aβ levels in both CSF and blood in adult and aged 5XFAD Alzheimer transgenic mice. Collectively, the synthetic Aβ injected into CSF immediately migrate to the aqueous humor, however, the age-dependently reducing pattern of Aβ levels in CSF and blood was not observed in the aqueous humor.

Klíčová slova:

Alzheimer's disease – Biomarkers – Blood – Blood plasma – Cerebrospinal fluid – Eyes – Intravenous injections – Mouse models


1. Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol Med. 2016;8(6):595–608. doi: 10.15252/emmm.201606210 27025652

2. Tarasoff-Conway JM, Carare RO, Osorio RS, Glodzik L, Butler T, Fieremans E, et al. Clearance systems in the brain-implications for Alzheimer disease. Nat Rev Neurol. 2015;11(8):457–70. doi: 10.1038/nrneurol.2015.119 26195256

3. Buchhave P, Minthon L, Zetterberg H, Wallin AK, Blennow K, Hansson O. Cerebrospinal fluid levels of beta-amyloid 1–42, but not of tau, are fully changed already 5 to 10 years before the onset of Alzheimer dementia. Arch Gen Psychiatry. 2012;69(1):98–106. doi: 10.1001/archgenpsychiatry.2011.155 22213792

4. Hillen H. The Beta Amyloid Dysfunction (BAD) Hypothesis for Alzheimer’s Disease. Frontiers in Neuroscience. 2019;13(1154).

5. Silverberg N, Elliott C, Ryan L, Masliah E, Hodes R. NIA commentary on the NIA-AA Research Framework: Towards a biological definition of Alzheimer's disease. Alzheimers Dement. 2018;14(4):576–8. doi: 10.1016/j.jalz.2018.03.004 29653608

6. Muller EG, Edwin TH, Stokke C, Navelsaker SS, Babovic A, Bogdanovic N, et al. Amyloid-beta PET-Correlation with cerebrospinal fluid biomarkers and prediction of Alzheimer s disease diagnosis in a memory clinic. PLoS One. 2019;14(8):e0221365. doi: 10.1371/journal.pone.0221365 31430334

7. Jack CR Jr., Barrio JR, Kepe V. Cerebral amyloid PET imaging in Alzheimer's disease. Acta Neuropathol. 2013;126(5):643–57. doi: 10.1007/s00401-013-1185-7 24100688

8. Lashley T, Schott JM, Weston P, Murray CE, Wellington H, Keshavan A, et al. Molecular biomarkers of Alzheimer's disease: progress and prospects. Dis Model Mech. 2018;11(5).

9. Lewczuk P, Esselmann H, Groemer TW, Bibl M, Maler JM, Steinacker P, et al. Amyloid beta peptides in cerebrospinal fluid as profiled with surface enhanced laser desorption/ionization time-of-flight mass spectrometry: evidence of novel biomarkers in Alzheimer's disease. Biol Psychiatry. 2004;55(5):524–30. doi: 10.1016/j.biopsych.2003.10.014 15023581

10. Niemantsverdriet E, Valckx S, Bjerke M, Engelborghs S. Alzheimer's disease CSF biomarkers: clinical indications and rational use. Acta Neurol Belg. 2017;117(3):591–602. doi: 10.1007/s13760-017-0816-5 28752420

11. Hampel H, Teipel SJ, Fuchsberger T, Andreasen N, Wiltfang J, Otto M, et al. Value of CSF beta-amyloid1-42 and tau as predictors of Alzheimer's disease in patients with mild cognitive impairment. Mol Psychiatry. 2004;9(7):705–10. doi: 10.1038/ 14699432

12. Lee JC, Kim SJ, Hong S, Kim Y. Diagnosis of Alzheimer's disease utilizing amyloid and tau as fluid biomarkers. Exp Mol Med. 2019;51(5):53. doi: 10.1038/s12276-019-0250-2 31073121

13. Carandini T, Arighi A, Sacchi L, Fumagalli GG, Pietroboni AM, Ghezzi L, et al. Testing the 2018 NIA-AA research framework in a retrospective large cohort of patients with cognitive impairment: from biological biomarkers to clinical syndromes. Alzheimers Res Ther. 2019;11(1):84. doi: 10.1186/s13195-019-0543-7 31615545

14. Evans RW. Complications of lumbar puncture. Neurol Clin. 1998;16(1):83–105. doi: 10.1016/s0733-8619(05)70368-6 9421542

15. Blennow K, Zetterberg H. The past and the future of Alzheimer's disease CSF biomarkers-a journey toward validated biochemical tests covering the whole spectrum of molecular events. Front Neurosci. 2015;9:345. doi: 10.3389/fnins.2015.00345 26483625

16. Deane R, Wu Z, Zlokovic BV. RAGE (yin) versus LRP (yang) balance regulates alzheimer amyloid beta-peptide clearance through transport across the blood-brain barrier. Stroke. 2004;35(11 Suppl 1):2628–31.

17. Takeda S, Sato N, Rakugi H, Morishita R. Plasma beta-amyloid as potential biomarker of Alzheimer disease: possibility of diagnostic tool for Alzheimer disease. Mol Biosyst. 2010;6(10):1760–6. doi: 10.1039/c003148h 20567751

18. Teunissen CE, Chiu MJ, Yang CC, Yang SY, Scheltens P, Zetterberg H, et al. Plasma Amyloid-beta (Abeta42) Correlates with Cerebrospinal Fluid Abeta42 in Alzheimer's Disease. J Alzheimers Dis. 2018;62(4):1857–63. doi: 10.3233/JAD-170784 29614646

19. Donohue MC, Moghadam SH, Roe AD, Sun CK, Edland SD, Thomas RG, et al. Longitudinal plasma amyloid beta in Alzheimer's disease clinical trials. Alzheimers Dement. 2015;11(9):1069–79. doi: 10.1016/j.jalz.2014.07.156 25301682

20. Lovheim H, Elgh F, Johansson A, Zetterberg H, Blennow K, Hallmans G, et al. Plasma concentrations of free amyloid beta cannot predict the development of Alzheimer's disease. Alzheimers Dement. 2017;13(7):778–82. doi: 10.1016/j.jalz.2016.12.004 28073031

21. Lewczuk P, Riederer P, O'Bryant SE, Verbeek MM, Dubois B, Visser PJ, et al. Cerebrospinal fluid and blood biomarkers for neurodegenerative dementias: An update of the Consensus of the Task Force on Biological Markers in Psychiatry of the World Federation of Societies of Biological Psychiatry. World J Biol Psychiatry. 2018;19(4):244–328. doi: 10.1080/15622975.2017.1375556 29076399

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. 2016;6:26801. doi: 10.1038/srep26801 27241045

23. Hart NJ, Koronyo Y, Black KL, Koronyo-Hamaoui M. Ocular indicators of Alzheimer's: exploring disease in the retina. Acta Neuropathol. 2016;132(6):767–87. doi: 10.1007/s00401-016-1613-6 27645291

24. Lim JK, Li QX, He Z, Vingrys AJ, Wong VH, Currier N, et al. The Eye As a Biomarker for Alzheimer's Disease. Front Neurosci. 2016;10:536. doi: 10.3389/fnins.2016.00536 27909396

25. Frederikse PH, Garland D, Zigler JS Jr., Piatigorsky J. Oxidative stress increases production of beta-amyloid precursor protein and beta-amyloid (Abeta) in mammalian lenses, and Abeta has toxic effects on lens epithelial cells. J Biol Chem. 1996;271(17):10169–74. doi: 10.1074/jbc.271.17.10169 8626578

26. Goldstein LE, Muffat JA, Cherny RA, Moir RD, Ericsson MH, Huang X, et al. Cytosolic beta-amyloid deposition and supranuclear cataracts in lenses from people with Alzheimer's disease. Lancet. 2003;361(9365):1258–65. doi: 10.1016/S0140-6736(03)12981-9 12699953

27. Moncaster JA, Pineda R, Moir RD, Lu S, Burton MA, Ghosh JG, et al. Alzheimer's disease amyloid-beta links lens and brain pathology in Down syndrome. PLoS One. 2010;5(5):e10659. doi: 10.1371/journal.pone.0010659 20502642

28. Koronyo Y, Salumbides BC, Black KL, Koronyo-Hamaoui M. Alzheimer's disease in the retina: imaging retinal abeta plaques for early diagnosis and therapy assessment. Neurodegener Dis. 2012;10(1–4):285–93. doi: 10.1159/000335154 22343730

29. La Morgia C, Ross-Cisneros FN, Koronyo Y, Hannibal J, Gallassi R, Cantalupo G, et al. Melanopsin retinal ganglion cell loss in Alzheimer disease. Ann Neurol. 2016;79(1):90–109. doi: 10.1002/ana.24548 26505992

30. Koronyo-Hamaoui M, Koronyo Y, Ljubimov AV, Miller CA, Ko MK, Black KL, et al. Identification of amyloid plaques in retinas from Alzheimer's patients and noninvasive in vivo optical imaging of retinal plaques in a mouse model. Neuroimage. 2011;54 Suppl 1:S204–17.

31. Dutescu RM, Li QX, Crowston J, Masters CL, Baird PN, Culvenor JG. Amyloid precursor protein processing and retinal pathology in mouse models of Alzheimer's disease. Graefes Arch Clin Exp Ophthalmol. 2009;247(9):1213–21. doi: 10.1007/s00417-009-1060-3 19271231

32. Colligris P, Perez de Lara MJ, Colligris B, Pintor J. Ocular Manifestations of Alzheimer's and Other Neurodegenerative Diseases: The Prospect of the Eye as a Tool for the Early Diagnosis of Alzheimer's Disease. J Ophthalmol. 2018;2018:8538573. doi: 10.1155/2018/8538573 30151279

33. Chowdhury UR, Madden BJ, Charlesworth MC, Fautsch MP. Proteome analysis of human aqueous humor. Invest Ophthalmol Vis Sci. 2010;51(10):4921–31. doi: 10.1167/iovs.10-5531 20463327

34. Cho SM, Kim HV, Lee S, Kim HY, Kim W, Kim TS, et al. Correlations of amyloid-beta concentrations between CSF and plasma in acute Alzheimer mouse model. Sci Rep. 2014;4:6777. doi: 10.1038/srep06777 25345439

35. Kim HY, Lee DK, Chung BR, Kim HV, Kim Y. Intracerebroventricular Injection of Amyloid-beta Peptides in Normal Mice to Acutely Induce Alzheimer-like Cognitive Deficits. J Vis Exp. 2016(109).

36. Liu L, Duff K. A technique for serial collection of cerebrospinal fluid from the cisterna magna in mouse. J Vis Exp. 2008(21).

37. Fortmann SD, Lorenc VE, Shen J, Hackett SF, Campochiaro PA. Mousetap, a Novel Technique to Collect Uncontaminated Vitreous or Aqueous and Expand Usefulness of Mouse Models. Sci Rep. 2018;8(1):6371. doi: 10.1038/s41598-018-24197-2 29686307

38. Ratnayaka JA, Serpell LC, Lotery AJ. Dementia of the eye: the role of amyloid beta in retinal degeneration. Eye (Lond). 2015;29(8):1013–26.

39. Shibata M, Yamada S, Kumar SR, Calero M, Bading J, Frangione B, et al. Clearance of Alzheimer's amyloid-ss(1–40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J Clin Invest. 2000;106(12):1489–99. doi: 10.1172/JCI10498 11120756

40. Bibl M, Welge V, Esselmann H, Wiltfang J. Stability of amyloid-beta peptides in plasma and serum. Electrophoresis. 2012;33(3):445–50. doi: 10.1002/elps.201100455 22287174

41. Kanekiyo T, Bu G. The low-density lipoprotein receptor-related protein 1 and amyloid-beta clearance in Alzheimer's disease. Front Aging Neurosci. 2014;6:93. doi: 10.3389/fnagi.2014.00093 24904407

42. Cho SM, Lee S, Yang SH, Kim HY, Lee MJ, Kim HV, et al. Age-dependent inverse correlations in CSF and plasma amyloid-beta(1–42) concentrations prior to amyloid plaque deposition in the brain of 3xTg-AD mice. Sci Rep. 2016;6:20185. doi: 10.1038/srep20185 26830653

43. Deane R, Bell RD, Sagare A, Zlokovic BV. Clearance of amyloid-beta peptide across the blood-brain barrier: implication for therapies in Alzheimer's disease. CNS Neurol Disord Drug Targets. 2009;8(1):16–30. doi: 10.2174/187152709787601867 19275634

44. Goel M, Picciani RG, Lee RK, Bhattacharya SK. Aqueous humor dynamics: a review. Open Ophthalmol J. 2010;4:52–9. doi: 10.2174/1874364101004010052 21293732

45. Liu P, Thomson BR, Khalatyan N, Feng L, Liu X, Savas JN, et al. Selective permeability of mouse blood-aqueous barrier as determined by (15)N-heavy isotope tracing and mass spectrometry. Proc Natl Acad Sci U S A. 2018;115(36):9032–7. doi: 10.1073/pnas.1807982115 30127000

46. Perumal N, Manicam C, Steinicke M, Funke S, Pfeiffer N, Grus FH. Characterization of the human aqueous humour proteome: A comparison of the genders. PLoS One. 2017;12(3):e0172481. doi: 10.1371/journal.pone.0172481 28273097

47. Danesh-Meyer HV, Levin LA. Glaucoma as a neurodegenerative disease. J Neuroophthalmol. 2015;35 Suppl 1:S22–8.

48. Wostyn P, Van Dam D, De Deyn PP. Alzheimer's disease and glaucoma: Look-alike neurodegenerative diseases. Alzheimers Dement. 2019;15(4):600–1. doi: 10.1016/j.jalz.2018.12.012 30713020

49. Tsolaki F, Gogaki E, Tiganita S, Skatharoudi C, Lopatatzidi C, Topouzis F, et al. Alzheimer's disease and primary open-angle glaucoma: is there a connection? Clin Ophthalmol. 2011;5:887–90. doi: 10.2147/OPTH.S22485 21760717

50. Mancino R, Martucci A, Cesareo M, Giannini C, Corasaniti MT, Bagetta G, et al. Glaucoma and Alzheimer Disease: One Age-Related Neurodegenerative Disease of the Brain. Curr Neuropharmacol. 2018;16(7):971–7. doi: 10.2174/1570159X16666171206144045 29210654

51. Guo L, Salt TE, Luong V, Wood N, Cheung W, Maass A, et al. Targeting amyloid-beta in glaucoma treatment. Proc Natl Acad Sci U S A. 2007;104(33):13444–9. doi: 10.1073/pnas.0703707104 17684098

52. Koronyo Y, Biggs D, Barron E, Boyer DS, Pearlman JA, Au WJ, et al. Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer's disease. JCI Insight. 2017;2(16).

53. Parnell M, Guo L, Abdi M, Cordeiro MF. Ocular manifestations of Alzheimer's disease in animal models. Int J Alzheimers Dis. 2012;2012:786494. doi: 10.1155/2012/786494 22666623

54. Bayer AU, Keller ON, Ferrari F, Maag KP. Association of glaucoma with neurodegenerative diseases with apoptotic cell death: Alzheimer's disease and Parkinson's disease. Am J Ophthalmol. 2002;133(1):135–7. doi: 10.1016/s0002-9394(01)01196-5 11755850

55. Mansouri K, Medeiros FA, Weinreb RN. Global rates of glaucoma surgery. Graefes Arch Clin Exp Ophthalmol. 2013;251(11):2609–15. doi: 10.1007/s00417-013-2464-7 24068439

56. Thompson J, Lakhani N. Cataracts. Prim Care. 2015;42(3):409–23. doi: 10.1016/j.pop.2015.05.012 26319346

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2020 Číslo 1