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Karis Little, María Llorián-Salvador, Ángel del Marco, Monica Garcia-Alloza, Rafael Simó, Alan W Stitt; Characterising retinal neurovascular dysfunction in a mouse model of Alzheimer’s disease combined with Type 2 diabetes. Invest. Ophthalmol. Vis. Sci. 2022;63(7):271 – F0316.
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© ARVO (1962-2015); The Authors (2016-present)
Type-2 diabetes (T2D) is associated with increased risk of Alzheimer’s disease (AD). Commonly affected pathways centre around the neurovascular unit (NVU). Glial pathology, neurodegeneration and vascular damage are hallmarks of both diabetic retinopathy (DR) and AD. Therefore, retinal pathology may be useful to understand brain changes in T2D and AD. We assessed retinal pathology in mice models of AD and T2D, and a crossed model of AD/T2D to understand the pathogenesis of this important co-morbidity.
The NVU was assessed in retinal tissue from WT, APP/PS1, db/db and APP/PS1xdb/db mice at 14 and 26 weeks old. Immunohistochemistry staining was carried out to assess gliosis (GFAP), acellular capillaries (Isolectin-B4/Collagen 4), and Müller cell potassium/ water homeostasis (Kir4.1, AQP4). Changes to neuronal populations were assessed by staining for Calbindin (Horizontal cells), Brn3a (Retinal Ganglion cells) and Cone-arrestin (Cone-photoreceptors).
We observed NVU dysfunction in APP/PS1xdb/db retina including significant Müller cell gliosis at 14 weeks (p<0.05). Müller cells showed alteration of Kir4.1 and AQP4 localisation in APP/PS1 and db/db retina which was more apparent in APP/PS1xdb/db mice at 26 weeks. APP/PS1 x db/db mice had significantly more acellular capillaries than WT mice at 14 weeks (p<0.01). A significant decrease in retinal ganglion cells was observed at 26 weeks in db/db (p<0.05) and APP/PS1 x db/db mice (p<0.05) compared to WT. Horizontal cells were significantly reduced in APP/PS1 (p<0.05) and APP/PS1xdb/db (p<0.05) retina at 26 weeks. A significant decrease in the number of Cone arrestin+ cells in the APP/PS1xdb/db retina was observed at both 14 (p<0.001) and 26 weeks (p<0.001) vs WT. The number of DAPI+ cells in the outer nuclear layer was significantly reduced in APP/PS1xdb/db mice compared to APP/PS1 (p<0.001) and db/db (p<0.05) alone.
We observed evidence of NVU dysfunction APP/PS1xdb/db retina, which appeared to be more severe than APP/PS1 or db/db alone. This occurs alongside severe cognitive impairment in this model (1). APP/PS1xdb/db had increased gliosis and dysregulation of water and ion homeostasis together with retinal neurodegeneration features. Further studies are required to characterise the changes of the NVU in the retina and brain during diabetes related neurodegeneration. (1) Infante-Garcia et al. 2016
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.
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