Amyloid Precursor Protein Processing and Retinal Pathology in Mouse Models of Alzheimer's Disease

Overview

Journal Graefes Arch Clin Exp Ophthalmol

Specialty Ophthalmology

Date 2009 Mar 10

PMID 19271231

Citations 72

Authors

R Michael Dutescu

Qiao-Xin Li

Jonathan Crowston

Colin L Masters

Paul N Baird

Janetta G Culvenor

Affiliations

Soon will be listed here.

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-beta (Abeta) 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 Abeta, whereas Abeta 42/40 levels were assayed by ELISA. APP and processed fragments were detected biochemically by Western blotting with domain-specific antibodies, using antibody WO2 (Abeta) and rabbit antibody 369 to the C-terminal domain of APP.

Results: Immunocytochemistry revealed strong cytoplasmic expression of APP and possibly Abeta 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 alpha-secretase generated C-terminal fragments in transgenic retinal tissues than beta-secretase-generated C-terminal fragments. Very low level Abeta was detected in transgenic retinas by ELISA; retinal Abeta 42 was 75 times less than for transgenic brain. Abeta was not detected in mouse retina by Western blotting in our study, indicating much less generation of Abeta 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 Abeta than found in brain.

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References

Iseri P, Altinas O, Tokay T, Yuksel N . Relationship between cognitive impairment and retinal morphological and visual functional abnormalities in Alzheimer disease. J Neuroophthalmol. 2006; 26(1):18-24. DOI: 10.1097/01.wno.0000204645.56873.26. View

Janciauskiene S, Krakau T . Alzheimer's peptide and serine proteinase inhibitors in glaucoma and exfoliation syndrome. Doc Ophthalmol. 2003; 106(3):215-23. DOI: 10.1023/a:1022949121078. View

Goldstein L, Muffat J, Cherny R, Moir R, Ericsson M, Huang X . 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. View

Yoshida T, Ohno-Matsui K, Ichinose S, Sato T, Iwata N, Saido T . The potential role of amyloid beta in the pathogenesis of age-related macular degeneration. J Clin Invest. 2005; 115(10):2793-800. PMC: 1201663. DOI: 10.1172/JCI24635. View

Bayer A, Keller O, Ferrari F . 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. View

Haass C, Lemere C, Capell A, Citron M, Seubert P, Schenk D . The Swedish mutation causes early-onset Alzheimer's disease by beta-secretase cleavage within the secretory pathway. Nat Med. 1995; 1(12):1291-6. DOI: 10.1038/nm1295-1291. View

Masters C, Simms G, Weinman N, Multhaup G, McDonald B, Beyreuther K . Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A. 1985; 82(12):4245-9. PMC: 397973. DOI: 10.1073/pnas.82.12.4245. View

Jankowsky J, Slunt H, Ratovitski T, Jenkins N, Copeland N, Borchelt D . Co-expression of multiple transgenes in mouse CNS: a comparison of strategies. Biomol Eng. 2001; 17(6):157-65. DOI: 10.1016/s1389-0344(01)00067-3. View

Guo L, Salt T, Luong V, Wood N, Cheung W, Maass A . Targeting amyloid-beta in glaucoma treatment. Proc Natl Acad Sci U S A. 2007; 104(33):13444-9. PMC: 1940230. DOI: 10.1073/pnas.0703707104. View

10.

IDA N, Hartmann T, Pantel J, Schroder J, Zerfass R, Forstl H . Analysis of heterogeneous A4 peptides in human cerebrospinal fluid and blood by a newly developed sensitive Western blot assay. J Biol Chem. 1996; 271(37):22908-14. DOI: 10.1074/jbc.271.37.22908. View

11.

Syed A, Armstrong R, Smith C . A quantitative analysis of optic nerve axons in elderly control subjects and patients with Alzheimer's disease. Folia Neuropathol. 2005; 43(1):1-6. View

12.

Evin G, Zhu A, Holsinger R, Masters C, Li Q . Proteolytic processing of the Alzheimer's disease amyloid precursor protein in brain and platelets. J Neurosci Res. 2003; 74(3):386-92. DOI: 10.1002/jnr.10745. View

13.

Holsinger R, McLean C, Beyreuther K, Masters C, Evin G . Increased expression of the amyloid precursor beta-secretase in Alzheimer's disease. Ann Neurol. 2002; 51(6):783-6. DOI: 10.1002/ana.10208. View

14.

Janciauskiene S, KRAKAU T . Alzheimer's peptide: a possible link between glaucoma, exfoliation syndrome and Alzheimer's disease. Acta Ophthalmol Scand. 2001; 79(3):328-9. DOI: 10.1034/j.1600-0420.2001.790327.x. View

15.

Mendez M, Mendez M, Martin R, Smyth K, Whitehouse P . Complex visual disturbances in Alzheimer's disease. Neurology. 1990; 40(3 Pt 1):439-43. DOI: 10.1212/wnl.40.3_part_1.439. View

16.

Vassar R, Bennett B, Kahn S, Mendiaz E, Denis P, Teplow D . Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science. 1999; 286(5440):735-41. DOI: 10.1126/science.286.5440.735. View

17.

Culvenor J, Henry A, Hartmann T, Evin G, Galatis D, Friedhuber A . Subcellular localization of the Alzheimer's disease amyloid precursor protein and derived polypeptides expressed in a recombinant yeast system. Amyloid. 1998; 5(2):79-89. DOI: 10.3109/13506129808995285. View

18.

Ning A, Cui J, To E, Ashe K, Matsubara J . Amyloid-beta deposits lead to retinal degeneration in a mouse model of Alzheimer disease. Invest Ophthalmol Vis Sci. 2008; 49(11):5136-43. PMC: 3947384. DOI: 10.1167/iovs.08-1849. View

19.

Ojima T, Tanabe T, Hangai M, Yu S, Morishita S, Yoshimura N . Measurement of retinal nerve fiber layer thickness and macular volume for glaucoma detection using optical coherence tomography. Jpn J Ophthalmol. 2007; 51(3):197-203. DOI: 10.1007/s10384-006-0433-y. View

20.

Trick G, Barris M . Abnormal pattern electroretinograms in patients with senile dementia of the Alzheimer type. Ann Neurol. 1989; 26(2):226-31. DOI: 10.1002/ana.410260208. View