Abstract
BackgroundIntensive light exposure and beta-amyloid (Aβ) 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 Aβ deposition mediates or exacerbates light exposure-induced pathogenesis of macular degeneration. Several studies including the one from us already showed accumulation of Aβ 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.ResultsHistopathological analysis has found significant loss of outer nuclear layer/photoreceptor outer segment and outer plexiform layer along with abnormal hypo- and 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 Aβ 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.ConclusionsOur 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 Aβ deposits might be an alternative animal model for AMD, if combined with other confounding factors such as intensive light exposure for AMD.
Highlights
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
In this study we examined the effects of constitutional expression of Ab deposits on retinal lesions induced by cyclic intensive light exposure (CILE) in the Human amyloid precursor protein with Swedish mutations (APPswe)/Presenilin 1 (PS1) bigenic mouse model of Alzheimer’s disease, and found that CILE significantly increased Ab deposition linked with Age-related macular degeneration (AMD)-like retinopathies in the transgenic mice
Cyclic intensive light exposure induces abnormal pigment deposition in retinal pigment epithelium (RPE), choroidal neovascularization (CNV) and degenerative changes in the retina of APPswe/PS1 bigenic mice To evaluate the effect of CILE on the retina of mice, the fundus was examined before and after CILE based on fundus photographs
Summary
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. It is unknown whether Ab deposition mediates or exacerbates light exposure-induced pathogenesis of macular degeneration. 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. Several groups of investigators including us demonstrate perivascular deposition of Ab in the retina in human CNV as well as different lines of Alzheimer’s-related transgenic mice [8,9]. 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 [17,18,19,20]
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