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Stuart L Graham, Nitin Chitranshi, Roger Chung, Vivek Kumar Gupta; Impaired inner retinal function and Amyloid β aggregation is demonstrated in a mouse model of Alzheimer’s disease. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2434.
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© ARVO (1962-2015); The Authors (2016-present)
Abnormal amyloid precursor protein (APP) expression and amyloid β (Aβ) deposition have been shown to be involved in the development of retinal ganglion cell apoptosis in glaucoma. The APP-PS1 mouse model of Alzheimer’s disease (AD) expresses several fold higher mutated human APP and PSEN1 transgenes compared to the endogenous murine APP. These mice exhibit age dependent Aβ plaque formation in their central nervous system. Here we evaluated Aβ aggregate formation in the retinas of these mice and compared it to WT animals. Intraocular pressure (IOP) in these transgenic animals was also evaluated. The impact of genetic modification and AD like pathology on the inner retinal function was investigated with electrophysiology.
Wild type and age-matched APP-PS1 transgenic littermates (13-16 month) were used to assess the inner retinal and whole retinal physiology using the scotopic threshold response (STR) and scotopic electroretinogram (ERG) respectively (n=20). Intraocular pressure was examined using rebound tonometer and averaged (iCare) (n=20). Retinas were flat-mounted under the microscope and Aβ deposition pattern investigated histologically using Thioflavin-S staining.
The genetic manipulation of APP-PS1 genes and resultant AD like pathology manifested itself in the form of a retinal phenotype depicting a preferential loss of STR amplitude in the transgenic animals compared to the wild type counterparts: 47.9 +/- 4.6 uV vs 72.8 +/- 2.3 uV (p<0.0001). Interestingly, the functional changes were also accompanied by slightly elevated IOP in these mice (p<0.0001). Thioflavin-S staining of the whole mounted retinas revealed a higher reactivity in APP-PS1 mice indicating greater Aβ deposition compared to the WT counterparts.
This study demonstrates that APP-PS1 mice have a compromised ganglion cell function as determined by reductions in STR. An interesting finding is a slightly elevated IOP, but the significance of this is not yet known. Further investigations will examine the relationship between Aβ aggregation and its impact on structure-function in the retina. This study highlights the need to understand any detrimental impact of AD on the inner retina and supports the concept of a potential overlap of the causal mechanisms in AD and glaucoma.
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