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Graefe's Archive for Clinical and Experimental Ophthalmology

Published in:

01-09-2009 | Pathology

Amyloid precursor protein processing and retinal pathology in mouse models of Alzheimer’s disease

Authors: R. Michael Dutescu, Qiao-Xin Li, Jonathan Crowston, Colin L. Masters, Paul N. Baird, Janetta G. Culvenor

Published in: Graefe's Archive for Clinical and Experimental Ophthalmology | Issue 9/2009

Abstract

Background

Retinal ganglion cell loss is considered to be a cause of visual impairment in Alzheimer`s patients. Alterations in amyloid precursor protein (APP) processing and amyloid-β (Aβ) accumulation, key molecules associated with Alzheimer`s disease pathogenesis, may therefore contribute to retinal damage. We therefore investigated retinal APP processing and eye morphology in Alzheimer`s transgenic mouse models.

Methods

Eyes and brain samples of 2- to 18-month-old transgenic mice expressing human APP with the double Swedish mutation (APPswe) (APP K595N/M596L)(Tg2576) were compared with eyes and brain tissue from wild-type background C57BL6xSJL controls. In addition, 6- to 12-month-old double transgenic mice over-expressing human APPswe and mutant presenilin 1 with exon 9 deletion (APPswe/PS1-dE9) were compared with background controls of C57BL6xC3H strain. Tissue samples were fixed in formalin for immunohistochemistry, and dissected retinal and cerebellar extracts were frozen for Western blotting and enzyme-linked immunosorbent assay (ELISA). Monoclonal antibodies 1E8 and WO2 were used for immunohistochemical detection of APP and Aβ, whereas Aβ 42/40 levels were assayed by ELISA. APP and processed fragments were detected biochemically by Western blotting with domain-specific antibodies, using antibody WO2 (Aβ) and rabbit antibody 369 to the C-terminal domain of APP.

Results

Immunocytochemistry revealed strong cytoplasmic expression of APP and possibly Aβ in retinal ganglion cells and inner nuclear layer cells, and in lens and corneal epithelia for APP transgenic mice. Retinas from the APP transgenic mouse strains contained 18 to 70 kDa APP proteolytic products that were not detected in the cerebellum. We found a higher proportion of APP α-secretase generated C-terminal fragments in transgenic retinal tissues than β-secretase-generated C-terminal fragments. Very low level Aβ was detected in transgenic retinas by ELISA; retinal Aβ 42 was 75 times less than for transgenic brain. Aβ was not detected in mouse retina by Western blotting in our study, indicating much less generation of Aβ in retina than brain tissue.

Conclusions

Alzheimer’s mouse model retinas present with different APP proteolytic products and have a significantly lower production of amyloidogenic Aβ than found in brain.

Mendez MF, Mendez MA, Martin R, Smyth KA, Whitehouse PJ (1990) Complex visual disturbances in Alzheimer’s disease. Neurology 40:439–443PubMed

Tippett WJ, Krajewski A, Sergio LE (2007) Visuomotor integration is compromised in Alzheimer’s disease patients reaching for remembered targets. Eur Neurol 58:1–114. doi:10.1159/000102160 PubMedCrossRef

Gary (1989) Abnormal pattern electroretinograms in patients with sede dementia of the alzheimer type. Ann Neurol 26:226–231CrossRef

Iseri PK, Altinas O, Tokay T, Yuksel N (2006) Relationship between cognitive impairment and retinal morphological and visual functional abnormalities in Alzheimer disease. J Neuroophthalmol 26:18–24. doi:10.1097/01.wno.0000204645.56873.26 PubMed

Ojima T, Tanabe T, Hangai M, Yu S, Morishita S, Yoshimura N (2007) Measurement of retinal nerve fiber layer thickness and macular volume for glaucoma detection using optical coherence tomography. Jpn J Ophthalmol 51:197–203. doi:10.1007/s10384–006-0433-y PubMedCrossRef

Bayer AU, Keller ON, Ferrari F, Maag KP (2002) Association of glaucoma with neurodegenerative diseases with apoptotic cell death: Alzheimer’s disease and Parkinson’s disease. Am J Ophthalmol 133:135–137. doi:10.1016/S0002-9394(01)01196-5 PubMedCrossRef

Syed AB, Armstrong RA, Smith CU (2005) A quantitative analysis of optic nerve axons in elderly control subjects and patients with Alzheimer’s disease. Folia Neuropathol 43:1–69PubMed

Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K (1985) Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci USA 82:4245–4249. doi:10.1073/pnas.82.12.4245 PubMedCrossRef

Hanger DP, Brion JP, Gallo JM, Cairns NJ, Luthert PJ, Anderton BH (1991) Tau in Alzheimer’s disease and Down’s syndrome is insoluble and abnormally phosphorylated. Biochem J 275(Pt 1):99–104PubMed

10.

Evin G, Weidemann A (2002) Biogenesis and metabolism of Alzheimer’s disease Abeta amyloid peptides. Peptides 23:1285–1297. doi:10.1016/S0196-9781(02)00063-3 PubMedCrossRef

11.

Janciauskiene S, Krakau T (2001) Alzheimer’s peptide: a possible link between glaucoma, exfoliation syndrome and Alzheimer’s disease. Acta Ophthalmol Scand 79:328–329. doi:10.1034/j.1600-0420.2001.790327.x PubMedCrossRef

12.

Janciauskiene S, Krakau T (2003) Alzheimer’s peptide and serine proteinase inhibitors in glaucoma and exfoliation syndrome. Doc Ophthalmol 106:215–223. doi:10.1023/A:1022949121078 PubMedCrossRef

13.

Yoshida T, Ohno-Matsui K, Ichinose S, Sato T, Iwata N, Saido TC, Hisatomi T, Mochizuki M, Morita I (2005) The potential role of amyloid beta in the pathogenesis of age-related macular degeneration. J Clin Invest 115:2793–2800. doi:10.1172/JCI24635 PubMedCrossRef

14.

Goldstein LE, Muffat JA, Cherny RA, Moir RD, Ericsson MH, Huang X, Mavros C, Coccia JA, Faget KY, Fitch KA, Masters CL, Tanzi RE, Chylack LT Jr, Bush AI (2003) Cytosolic beta-amyloid deposition and supranuclear cataracts in lenses from people with Alzheimer’s disease. Lancet 361:1258–1265. doi:10.1016/S0140-6736(03)12981-9 PubMedCrossRef

15.

Guo L, Salt TE, Luong V, Wood N, Cheung W, Maass A, Ferrari G, Russo-Marie F, Sillito AM, Cheetham ME, Moss SE, Fitzke FW, Cordeiro MF (2007) Targeting amyloid-beta in glaucoma treatment. Proc Natl Acad Sci USA 104:13444–13449. doi:10.1073/pnas.0703707104 PubMedCrossRef

16.

Goldblum D, Kipfer-Kauer A, Sarra GM, Wolf S, Frueh BE (2007) Distribution of amyloid precursor protein and amyloid-beta immunoreactivity in DBA/2J glaucomatous mouse retinas. Invest Ophthalmol Vis Sci 48:5085–5090. doi:10.1167/iovs.06-1249 PubMedCrossRef

17.

Haass C, Lemere CA, Capell A, Citron M, Seubert P, Schenk D, Lannfelt L, Selkoe DJ (1995) The Swedish mutation causes early-onset Alzheimer’s disease by beta-secretase cleavage within the secretory pathway. Nat Med 1:1291–1296. doi:10.1038/nm1295-1291 PubMedCrossRef

18.

Prihar G, Verkkoniem A, Perez-Tur J, Crook R, Lincoln S, Houlden H, Somer M, Paetau A, Kalimo H, Grover A, Myllykangas L, Hutton M, Hardy J, Haltia M (1999) Alzheimer disease PS-1 exon 9 deletion defined. Nat Med 5:1090. doi:10.1038/13383 PubMedCrossRef

19.

Ning A, Cui JZ, To E, Hsiao Ashe K, Matsubara JA (2008) Amyloid beta deposits lead to retinal degeneration in a mouse model of alzheimer disease. Invest Ophthalmol Vis Sci

20.

Shimazawa M, Inokuchi Y, Okuno T, Nakajima Y, Sakaguchi G, Kato A, Oku H, Sugiyama T, Kudo T, Ikeda T, Takeda M, Hara H (2008) Reduced retinal function in amyloid precursor protein-over-expressing transgenic mice via attenuating glutamate-N-methyl-d-aspartate receptor signaling. J Neurochem 107:279–290. doi:10.1111/j.1471-4159.2008.05606.x PubMedCrossRef

21.

Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G (1996) Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 274:99–102. doi:10.1126/science.274.5284.99 PubMedCrossRef

22.

Jankowsky JL, Slunt HH, Ratovitski T, Jenkins NA, Copeland NG, Borchelt DR (2001) Co-expression of multiple transgenes in mouse CNS: a comparison of strategies. Biomol Eng 17:157–165. doi:10.1016/S1389-0344(01)00067-3 PubMedCrossRef

23.

Ida N, Hartmann T, Pantel J, Schroder J, Zerfass R, Forstl H, Sandbrink R, Masters CL, Beyreuther K (1996) Analysis of heterogeneous A4 peptides in human cerebrospinal fluid and blood by a newly developed sensitive Western blot assay. J Biol Chem 271:22908–22914. doi:10.1074/jbc.271.37.22908 PubMedCrossRef

24.

Buxbaum JD, Gandy SE, Cicchetti P, Ehrlich ME, Czernik AJ, Fracasso RP, Ramabhadran TV, Unterbeck AJ, Greengard P (1990) Processing of Alzheimer beta/A4 amyloid precursor protein: modulation by agents that regulate protein phosphorylation. Proc Natl Acad Sci USA 87:6003–6006. doi:10.1073/pnas.87.15.6003 PubMedCrossRef

25.

Culvenor JG, Henry A, Hartmann T, Evin G, Galatis D, Friedhuber A, Jayasena UL, Underwood JR, Beyreuther K, Masters CL, Cappai R (1998) Subcellular localization of the Alzheimer’s disease amyloid precursor protein and derived polypeptides expressed in a recombinant yeast system. Amyloid 5:79–89PubMed

26.

Fodero-Tavoletti MT, Smith DP, McLean CA, Adlard PA, Barnham KJ, Foster LE, Leone L, Perez K, Cortes M, Culvenor JG, Li QX, Laughton KM, Rowe CC, Masters CL, Cappai R, Villemagne VL (2007) In vitro characterization of Pittsburgh compound-B binding to Lewy bodies. J Neurosci 27:10365–10371. doi:10.1523/JNEUROSCI.0630-07.2007 PubMedCrossRef

27.

Culvenor JG, McLean CA, Cutt S, Campbell BC, Maher F, Jakala P, Hartmann T, Beyreuther K, Masters CL, Li QX (1999) Non-Abeta component of Alzheimer’s disease amyloid (NAC) revisited. NAC and alpha-synuclein are not associated with Abeta amyloid. Am J Pathol 155:1173–1181PubMed

28.

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 286:735–741. doi:10.1126/science.286.5440.735 PubMedCrossRef

29.

Holsinger RM, McLean CA, Beyreuther K, Masters CL, Evin G (2002) Increased expression of the amyloid precursor beta-secretase in Alzheimer’s disease. Ann Neurol 51:783–786. doi:10.1002/ana.10208 PubMedCrossRef

30.

Lehman EJ, Kulnane LS, Lamb BT (2003) Alterations in beta-amyloid production and deposition in brain regions of two transgenic models. Neurobiol Aging 24:645–653. doi:10.1016/S0197-4580(02)00153-7 PubMedCrossRef

31.

Evin G, Zhu A, Holsinger RM, Masters CL, Li QX (2003) Proteolytic processing of the Alzheimer’s disease amyloid precursor protein in brain and platelets. J Neurosci Res 74:386–392. doi:10.1002/jnr.10745 PubMedCrossRef

32.

Paquet C, Boissonnot M, Roger F, Dighiero P, Gil R, Hugon J (2007) Abnormal retinal thickness in patients with mild cognitive impairment and Alzheimer’s disease. Neurosci Lett 420:97–99. doi:10.1016/j.neulet.2007.02.090 PubMedCrossRef

Title: Amyloid precursor protein processing and retinal pathology in mouse models of Alzheimer’s disease
Authors: R. Michael Dutescu
Qiao-Xin Li
Jonathan Crowston
Colin L. Masters
Paul N. Baird
Janetta G. Culvenor
Publication date: 01-09-2009
Publisher: Springer-Verlag
Published in: Graefe's Archive for Clinical and Experimental Ophthalmology / Issue 9/2009
Print ISSN: 0721-832X
Electronic ISSN: 1435-702X
DOI: https://doi.org/10.1007/s00417-009-1060-3

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Amyloid precursor protein processing and retinal pathology in mouse models of Alzheimer’s disease

Abstract

Background

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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