Topical ocular administration of the GLP-1 receptor agonist liraglutide arrests hyperphosphorylated tau-triggered diabetic retinal neurodegeneration via activation of GLP-1R/Akt/GSK3β signaling

Diabetic retinal neurodegeneration, in particular synaptic neurodegeneration of retinal ganglion cells (RGCs) occurring before RGCs apoptosis, may represent the earliest event in the pathogenesis of diabetic retinopathy (DR). Our previous study identified hyperphosphorylated-tau as a critical toxic mediator in diabetic RGCs synaptic neurodegeneration. Thus, therapeutic agents targeting to tau may appear as a promising strategy to arrest the progression of DR. The glucagon-like-peptide 1 receptor (GLP-1R) agonists, including liraglutide, can ameliorate neurodegenerative features in models of Alzheimer's disease and diabetes by decreasing tau hyperphosphorylation in the brain. Liraglutide has also been found to prevent retinal neural apoptosis/loss in diabetic mice. However, whether liraglutide can prevent diabetic synapse degeneration of RGCs, and its neuroprotective role, if any, is due to alleviating retinal tau hyperphosphorylation remain unknown. Here, using a well characterized high-fat diet (HFD)-induced diabetes mouse model, we showed that topical ocular administration of liraglutide reversed hyperphosphorylated tau-triggered RGCs synaptic degeneration in HFD-induced diabetes. The neuroprotective effect of liraglutide on diabetic retinae was abolished when GLP-1R or Akt was inhibited by topically co-administration with a GLP-1R antagonist, exendin-(9–39), or an Akt inhibitor MK2206, respectively. However, knock-down of GSK3β by intravitreal injection of si-GSK3β restored the neuroprotective effects of liraglutide abrogated by Akt inactivation. Thus, our present study demonstrated that liraglutide can arrest hyperphosphorylated tau-triggered retinal neurodegeneration via activation of GLP-1R/Akt/GSK3β signaling. Our results also propose that topical ocular application of liraglutide can be envisaged as a potentially useful strategy for the treatment of retinal tauopathy at the early onset of DR.