Neuronal Epac1 mediates retinal neurodegeneration in mouse models of ocular hypertension

Abstract

Progressive loss of retinal ganglion cells (RGCs) leads to irreversible visual deficits in glaucoma. Here, we found that the level of cyclic AMP and the activity and expression of its mediator Epac1 were increased in retinas of two mouse models of ocular hypertension. Genetic depletion of Epac1 significantly attenuated ocular hypertension–induced detrimental effects in the retina, including vascular inflammation, neuronal apoptosis and necroptosis, thinning of ganglion cell complex layer, RGC loss, and retinal neuronal dysfunction. With bone marrow transplantation and various Epac1 conditional knockout mice, we further demonstrated that Epac1 in retinal neuronal cells (especially RGCs) was responsible for their death. Consistently, pharmacologic inhibition of Epac activity prevented RGC loss. Moreover, in vitro study on primary RGCs showed that Epac1 activation was sufficient to induce RGC death, which was mechanistically mediated by CaMKII activation. Taken together, these findings indicate that neuronal Epac1 plays a critical role in retinal neurodegeneration and suggest that Epac1 could be considered a target for neuroprotection in glaucoma.

AIBP protects retinal ganglion cells against neuroinflammation and mitochondrial dysfunction in glaucomatous neurodegeneration

“…To determine whether elevated pressure alters expression level of AIBP in murine RGCs, we first transiently induced acute IOP elevation in the eye of normal C57BL/6J mice by the cannulation of the anterior chamber of the eye, which was elevated to maintain an IOP of 70–80 mmHg for 50 min [ 24 ]. This model is also widely used by others to determine RGC death and survival in degenerative retinal diseases including acute glaucoma [ 14 , 38 ]. We found that elevated IOP significantly reduced Apoa1bp gene and AIBP protein expression in the retina at 24 h compared with sham control retina ( Fig.…”

Early alterations of neurovascular unit in the retina in mouse models of tauopathy

“…Mouse eyes were topically dilated with one drop of tropicamide and phenylephrine. Eyes were imaged using Spectral Domain Ophthalmic Imaging System (Envisu R2200, Bioptigen Inc., NC) as described previously [ 41 – 43 ]. Annular scans consisted of 1000 A-scans × 100 B-scans covering a donut-shaped area centered at the optic nerve disc were performed in order to remove variance of optic nerve head measurement.…”

“…ERG analysis was performed as described previously [ 26 , 41 , 43 ]. Briefly, mice were dark-adapted overnight and anesthetized via intraperitoneal injection with a mixture of ketamine (100 mg/kg) and xylazine (10 mg/kg).…”

Role of EPAC1 Signalosomes in Cell Fate: Friends or Foes?

“…In the nervous system, recent work from Liu’s laboratory found that EPAC1 deletion protected against retinal neuronal apoptosis and necroptosis after retinal I/R injury [ 8 ] In line with a neuroprotective effect of EPAC1 inhibition, Suzuki and colleagues found that stimulation of EPAC1 in cortical neurons increased apoptosis, Bax/BCL-2 ratio, and Bim/Bcl-2 interactions [ 90 ]. In addition, in vivo injection of an irreversible inhibitor of mitochondria complex II, 3-nitropropionic acid failed to promote neuronal apoptosis in EPAC1 KO mice [ 90 ].…”

“…EPAC1 is ubiquitously expressed and its potential involvement in central and peripheral diseases has been largely studied in recent years. For instance, EPAC1 has been linked to Alzheimer’s disease, depression, and retinal neurodegeneration [ 8 , 9 ]. EPAC1 is also involved in migration, proliferation, and apoptosis in several types of cancers [ 9 , 10 , 11 , 12 ].…”