Purchase this article with an account.
M.M. Walsh, G. Malek, P. Saloupis, P.M. Sullivan, B. Mace, D.E. Schmechel, C.B. Rickman, D.W. Rickman; Apolipoprotein (APOE) Allelic Expression, Advanced Age, and Diet Contribute to Atrophic Degenerative Changes in Retinal Ganglion Cells and Optic Nerve in a Mouse Model: Predictors of Severity of Glaucoma? . Invest. Ophthalmol. Vis. Sci. 2005;46(13):1241.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Purpose: To determine if known risk factors for Alzheimer's disease (AD): APOE genotype, advanced age, and diet, contribute to atrophic degenerative changes in retinal ganglion cells and the optic nerve. Methods: We used transgenic mice with targeted replacement of the mouse apoE gene with one of three human alleles, E2, E3, OR E4 under control of mouse apoE regulatory elements. Eighty wk old mice were fed a high–fat, cholate–enriched (to increase cholesterol absorption) diet for 8 wk. After euthanasia, blood samples were collected, and eyes and optic nerves were processed for immunohistochemistry with antibodies to glial fibrillary acidic protein (GFAP), mitogen–activated protein kinase (MAPK), tau protein, phosphorylated tau (AT8), or phosphorylated 200 kD neurofilament protein (P–NFP). Results: Blood analysis showed differential serum cholesterol levels both pre– and (post)–diet: E2 175 (275) mg/dl, E3 50 (150), E4 75 (200) mg/dl. E2 animals have intrinsic hyperlioproteinemia. Approximately 25% of E4 animals displayed morphological and immunohistochemical changes consistent with neurodegeneration. Analysis of optic nerves revealed a collagenous increase in the thickness of the endothelial cell basement membranes in some E4 animals and a marked increase of GFAP immunoreactivity was noted in optic nerve astrocytes and retinal Muller cells. In addition, ganglion cells in some E4 animals displayed punctate, cytoplasmic MAPK and AT8 immunoreactivity. Finally, some E4s showed increased immunostaining for P–NFP in ganglion cells bodies, dendrites, and proximal axon segments in the nerve fiber layer and optic nerve head. No appreciable immunostaining was observed in E2 or E3 retinas or optic nerves. Conclusions: E4 animals displayed ocular pathologies similar to those seen in AD.These include alterations at the level of the blood–brain barrier in the optic nerve, accumulation of glial filaments at the optic nerve head, and abnormal accumulation of phosphorylated filaments in ganglion cell bodies and dendrites. Changes in these structures, known to be altered in glaucoma, suggest that known risk factors, independent of intraocular pressure, may underlie the severity of glaucomatous damage.
This PDF is available to Subscribers Only