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Malia Edwards, D. McLeod, Raquel Gutierrez-Lanza, Jose Rodriguez Arellano, Gerard Lutty; Retinal glial changes in Alzheimer’s disease. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5596.
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© ARVO (1962-2015); The Authors (2016-present)
The retinas of both Alzheimer’s disease (AD) patients and transgenic AD models have amyloid deposits and ganglion cell degeneration (Hinton et al, N Engl J Med 1986; 315:485-7; Koronyo-Hamaoui M et al, Neuroimage 2011; 54 Suppl 1:S204-17; Ning A et al, Invest Ophthalmol Vis Sci 2008; 49:5136-43). Little is known, however, about changes to glial cells in the AD retina. This study used a triple transgenic mouse model (3TG-AD), with induced mutations in the amyloid precursor, tau, and presenilin 1 genes (Oddo S et al, Neuron 2003; 39:409-21), to investigate retinal glial changes in AD.
Animals were bred and housed at Zamudio Technological Park according to ARVO animal use standards. Mice were perfusion fixed and enucleated eyes washed in phosphate buffer. Control (NTG) and 3TG-AD retinal flatmounts were immunohistochemically labeled with GFAP and S100a/b antibodies. Images were taken with a Zeiss 710 Meta confocal microscope equipped with Zen software.
In both the NTG and 3TG-AD retinas, GFAP was expressed primarily by astrocytes. As early as 9M, a large subpopulation of 3TG-AD Müller cells had GFAP throughout their radial processes and endfeet. By 18M, most 3TG-AD Müller cells were GFAP-positive. S100a/b was also expressed by astrocytes in both the NTG and 3TG-AD retinas. While this protein was found throughout these cells, it was most prominent in the nuclei. Interestingly, this nuclear localization was less prominent in older NTG animals (18M or older) and the 3TG-AD retinas (12M or older), suggesting the secretion of this protein. S100 was found in some NTG Müller cell radial processes beginning at 12M but overall it was more diffuse and less prominent in the nuclei in the 3TG-AD retinas. There was also an age-dependent increase in Müller cell expression of S100 in 3TG-AD beginning at 9M. As early as 9M, several abnormal structures enveloped by GFAP and S100-positive astrocytes and lectin-positive cells were observed in the ganglion cell layer and throughout the inner retinas of 3TG-AD mice. While the glial envelopment is similar to that seen in amyloid deposits, further investigation is needed to identify these structures.
The results herein indicate an activation of glia in the 3TG-AD retina similar to that observed in the AD brain. It is important to now identify whether glial activation observed is associated with the formation of plaques and retinal degeneration in this model of AD.
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