Title Cyclic intensive light exposure induces retinal lesions similar to age-related macular degeneration in APPswe / PS 1 bigenic mice

Background: Intensive light exposure and beta-amyloid (Ab) aggregates have been known as a risk factor for macular degeneration and an important component in the pathologic drusen structure involved in this disorder, respectively. However, it is unknown whether Ab deposition mediates or exacerbates light exposure-induced pathogenesis of macular degeneration. Several studies including the one from us already showed accumulation of Ab deposits in the retina in Alzheimer’s transgenic mice. Using histopathological analysis combined with electroretinographic functional assessment, we investigated the effects of cyclic intensive light exposure (CILE) on the architecture of retina and related function in the APPswe/PS1bigenic mouse. Results: Histopathological analysis has found significant loss of outer nuclear layer/photoreceptor outer segment and outer plexiform layer along with abnormal hypoand hyper-pigmentation in the retinal pigment epithelium (RPE), remarkable choroidal neovascularization (CNV), and exaggerated neuroinflammatory responses in the outer retina of APPswe/PS1 bigenic mice following cyclic intensive light exposure (CILE), whereas controls remained little change contrasted with age-matched non-transgenic littermates. CILE-induced degenerative changes in RPE are further confirmed by transmission electron microcopy and manifest as formation of basal laminar deposits, irregular thickening of Bruch’s membrane (BrM), deposition of outer collagenous layer (OCL) in the subretinal space, and vacuolation in the RPE. Immunofluorescence microscopy reveals drusenoid Ab deposits in RPE as well as neovessels attached which are associated with disruption of RPE integrity and provoked neuroinflammatory response as indicated by markedly increased retinal infiltration of microglia. Moreover, both immunohistochemistry and Western blots detect an induction of vascular endothelial growth factor (VEGF) in RPE, which corroborates increased CNV in the outer retina in the bigenic mice challenged by CILE. Conclusions: Our findings demonstrate that degenerative changes in the outer retina in the APPswe/PS1 bigenic mouse induced by CILE are consistent with these in AMD. These results suggest that an Alzheimer’s transgenic animal model with accumulation of Ab deposits might be an alternative animal model for AMD, if combined with other confounding factors such as intensive light exposure for AMD. Background Age-related macular degeneration (AMD) is a degenerative disease in the eye, which causes irreversible blindness in elderly and is one of the major causes of blindness in developed countries [1]. Drusen and choroidal neovascularization (CNV) are the two pathological hallmarks of AMD, of which drusen accumulates in the subretinal pigment epithelium (RPE) space and CNV is characterized by new angiogensis from choroidal blood vessels which break through Bruch’s membrane (BrM) and RPE layer and is often associated with subretinal hemorrhage [2]. Recent studies suggest that betaamyloid (Ab) peptide, a major molecular signature in the brain of Alzheimer’s disease, might play an important role in the pathogenesis of AMD [3]. Ab aggregates have been identified as one of the major components in * Correspondence: tanz@uci.edu; gejian@mail.sysu. edu.cn State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China Department of Neurology, University of California Irvine School of Medicine, Irvine, CA 92697, USA Full list of author information is available at the end of the article Dong et al. BMC Neuroscience 2012, 13:34 http://www.biomedcentral. com/1471-2202/13/34 © 2012 Dong et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. drusen as well as in RPE cells in the retina of AMD [4-7]. Similarly to the brain, several groups of investigators including us also demonstrate perivascular deposition of Ab in the retina in human CNV as well as different lines of Alzheimer’s-related transgenic mice [8,9]. Importantly, immunotherapy that targets Ab significantly attenuated retinal lesions and improved retinal function in an AMD mouse model [10,11]. Moreover, growing evidence has indicated smoking [12], extensive sun light exposure [13], and ageing [14] as important risk factors for AMD. CILE is detrimental to the BrM, RPE, photoreceptor and other retinal structures due to induction of the reactive oxygen species and inflammatory response [15,16]. CILE induced drusen formation or stimulated CNV through upregulation of vascular endothelial growth factor (VEGF) as well as induction of oxidative stress in rodent models [17-20]. Nevertheless, the molecular basis of the pathogenesis of AMD, particularly about the role of Ab deposition in the development of RPE lesions and CNV, remains elusive. In this study we examined the effects of constitutional expression of Ab deposits on retinal lesions induced by CILE in the APPswe/PS1 bigenic mouse model of Alzheimer’s disease, and found that CILE significantly increased Ab deposition linked with AMD-like retinopathies in the transgenic mice. By contrast, there were no significant changes in the retina of either non-transgenic mice received equal light exposure or age-matched transgenic control.