Introduction:

Type-2 diabetes (T2D) is associated with an increased risk of cognitive impairment and Alzheimer’s disease (AD) and it is likely that there are common pathways involved in progressive dysfunction of the brain and retina neurovascular unit (NVU). Glial pathology, neurodegeneration and vascular closure are hallmarks of both diabetic retinopathy and AD and, therefore, retinal pathology may be useful to understand brain changes occurring in both T2D and AD. This study assessed retinal pathology in mice models of AD and T2D, and a crossed model of AD and T2D to understand the pathogenesis of this important co-morbidity, especially as it relates to the NVU.  

Methods:

The NVU was assessed in retinal tissue from WT, APP/PS1, db/db and APP/PS1 x db/db mice at 14 and 26 weeks of age (n=4-6 mice per group). Immunohistochemistry was carried out to assess gliosis (GFAP), acellular capillaries (Isolectin-B4/Collagen 4), and Müller cell potassium and water homeostasis (Kir4.1, AQP4). In addition, changes to neuronal populations were assessed by staining for PKC-α (Rod bipolar cells), Calbindin (Horizontal cells), Brn3a (Retinal Ganglion cells) and cone-arrestin (Cone-photoreceptors).

Results:

We observed evidence of NVU dysfunction in the retina of APP/PS1 x db/db mice including significant Müller cell gliosis at 14 weeks (p<0.05). In addition, Müller cells showed alteration of Kir4.1 and AQP4 localisation in APP/PS1, db/db and APP/PS1 x db/db mice at 26 weeks. APP/PS1 x db/db mice also had significantly more acellular capillaries than WT mice at 14 weeks (p<0.01). NVU dysfunction in the APP/PS1xdb/db retina appears to affect photoreceptors, as a significant decrease in the number of Cone arrestin⁺ cells was observed at both 14 (p<0.001) and 26 weeks (p<0.001) when compared to age-matched WT mice. Additionally, 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) when compared to WT retina.

Conclusions:

Overall, we observed evidence of NVU dysfunction in the retina of APP/PS1 x db/db mice. This occurs alongside severe cognitive impairment in this model. APP/PS1 x db/db had Increased gliosis and dysregulation of water and ion homeostasis together with retinal neurodegeneration features such as decreased photoreceptors, horizontal and retinal ganglion cells. Further studies are required to characterise the changes of the NVU in the retina and brain during diabetes related neurodegeneration.