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M. F. Cordeiro, L. Guo, K. M. Coxon, J. Duggan, S. Nizari, E. M. Normando, S. L. Sensi, F. W. Fitzke, T. E. Salt, S. E. Moss; Retinal Neurodegeneration in Alzheimer's Disease - Novel in vivo Assessment of Triple Transgenic Model. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3843.
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© ARVO (1962-2015); The Authors (2016-present)
The triple transgenic AD model (3xTg-AD) is an increasingly used model of Alzheimer’s Disease (AD) which is unique in exhibiting both Abeta and tau neuropathology. Despite the growing evidence of retinal involvement in AD, the 3xTg-AD model has not until now been ophthalmically investigated. Here, we examine the retina of 3xTg-AD mice in vivo, and assess patterns of retinal nerve cell death
,3xTg-AD (4 eyes, 14 months) and control PS1KI (2 eyes, female 18 months) mice were given IR-labelled annexin (1ml, 0.25 mg/ml, Annexin-IR for apoptosis) and Propidium Iodide (1ml, 0.4 mg/ml, PI) intravitreally. Some eyes were additionally assessed after inducing oxidative stress using intravitreal phorbol myristate acetate (1 ml, 10 mg/ml PMA). Imaging was performed using the fluorescein angiogram (488 nm argon laser) and indocyanine green (IR 790 nm diode laser) settings on a modified cSLO (Heidelberg Retina Angiograph 2). Dual-color images (red (PI) and green (IR annexin) channels of an RGB colour image) were obtained and analysed using ImageJ software with specific plugins for co-localisation (JaCoP and Intensity Correlation Analysis).
All eyes showed the presence of apoptosis. However, quantification of co-localisation showed significantly more RGCs in the early phase of apoptosis (P<0.05, annexin only staining ) and relatively fewer necrotic cells (P<0.05, PI staining only) in the 3xTg-AD model compared with control. In PMA treated eyes, there were significant levels of increased early apoptosis (P<0.05) and decreased late apoptosis (P<0.05, annexin and PI staining) in the 3xTg-AD model. PMA also increased the level of early apoptosis in aged control animals (P<0.05), although not to the same extent (30.3% in aged control as opposed to 61.4% in 3xTg-AD).
We demonstrate for the first time and in vivo, retinal pathology in the 3xTg-AD. We also show that although a low level of apoptotic and necrotic cell death occurs as a correlate of normal healthy ageing in mice, in AD mice, there is a significant increase in the relative numbers of RGCs in early-phase apoptosis. Furthermore, our results with PMA suggest that AD susceptibility to oxidative stress is increased compared to age-matched controls. We believe the retina provides an ideal tool for the quantitative monitoring of disease mechanisms and dynamics in experimental neurodegeneration.
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