Beta Amyloid and Retinal Ganglion Cell Apoptosis: Implications and Applications to Glaucoma

Abstract

Purpose: : The Alzheimer protein Beta Amyloid (Abeta) has been implicated in the development of retinal ganglion cell (RGC) apoptosis in glaucoma. A recent hypothesis has been that raised IOP leads to Abeta–related RGC apoptosis just as repeated exposures to increased intracranial pressure may contribute to neurodegeneration in a subset of Alzheimer's Disease. In this study, using in vivo rat models, we have firstly investigated Abeta expression in relation to elevated IOP, and secondly studied the effects of exogenous (intravitreal) Abeta on RGC apoptosis.

Methods: : We assessed a rat model of chronic ocular hypertension (OHT, n=20) as previously described, in which animals were killed at set intervals up to 16 weeks after elevated IOP. Eyes were examined histologically for RGC apoptosis and expression of Abeta (Biosource anti–Abeta antibody). A further group of DA rats (Abeta, n=20) were assessed following administration of intravitreal Abeta _25–35 (0 – 50 nmol; Sigma UK) under general anaesthesia. Rat eyes were imaged from 2 to 48 hours after injections using our recently developed method of imaging RGC apoptosis in vivo, with fluorescent–labelled annexin 5. After the final imaging, animals were killed and the eyes examined histologically.

Results: : We confirmed that RGC apoptosis in OHT model was positively correlated to the integral IOP (p<0.001). Abeta expression in the retinal ganglion cell layer was significantly increased compared to baseline at 2 and 8 weeks (p< 0.05) after IOP elevation, whereas peak RGC apoptosis was found to occur at 3 weeks. Intravitreal Abeta induced significant RGC apoptosis in a concentration dependent manner with maximal RGC apoptosis at 50 nmol, and at 16 hours, compared to control (p<0.01).

Conclusions: : Our results strongly suggest Abeta to be involved in the development of RGC apoptosis and neurodegeneration in glaucoma. Furthermore, this study demonstrates for the first time in vivo that application of Abeta _25–35 induces significant RGC apoptosis. This model may provide an useful tool in the investigation and treatment of not only glaucoma but all neurodegenerative processes, where our findings could enhance the clinical diagnosis and refine therapeutic intervention.

Keywords: apoptosis/cell death • imaging methods (CT, FA, ICG, MRI, OCT, RTA, SLO, ultrasound) • intraocular pressure