ABSTRACT: The amyloid beta (A?) pathway is strongly implicated in neurodegenerative conditions such as Alzheimer's disease and more recently, glaucoma. Here, we identify the ?2 adrenergic receptor agonists (?2ARA) used to lower intraocular pressure can prevent retinal ganglion cell (RGC) death via the non-amyloidogenic A?-pathway. Neuroprotective effects were confirmed in vivo and in vitro in different glaucoma-related models using ?2ARAs brimonidine (BMD), clonidine (Clo) and dexmedetomidine. ?2ARA treatment significantly reduced RGC apoptosis in experimental-glaucoma models by 97.7% and 92.8% (BMD, P<0.01) and 98% and 92.3% (Clo, P<0.01)) at 3 and 8 weeks, respectively. A reduction was seen in an experimental A?-induced neurotoxicity model (67% BMD and 88.6% Clo, both P<0.01, respectively), and in vitro, where ?2ARAs significantly (P<0.05) prevented cell death, under both hypoxic (CoCl2) and stress (UV) conditions. In experimental-glaucoma, BMD induced ninefold and 25-fold and 36-fold and fourfold reductions in A? and amyloid precursor protein (APP) levels at 3 and 8 weeks, respectively, in the RGC layer, with similar results with Clo, and in vitro with all three ?2ARAs. BMD significantly increased soluble APP? (sAPP?) levels at 3 and 8 weeks (2.1 and 1.6-fold) in vivo and in vitro with the CoCl2 and UV-light insults. Furthermore, treatment of UV-insulted cells with an sAPP? antibody significantly reduced cell viability compared with BMD-treated control (52%), co-treatment (33%) and untreated control (27%). Finally, we show that ?2ARAs modulate levels of laminin and MMP-9 in RGCs, potentially linked to changes in A? through APP processing. Together, these results provide new evidence that ?2ARAs are neuroprotective through their effects on the A? pathway and sAPP?, which to our knowledge, is the first description. Studies have identified the need for ?-secretase activators and sAPP?-mimetics in neurodegeneration; ?2ARAs, already clinically available, present a promising therapy, with applications not only to reducing RGC death in glaucoma but also other neurodegenerative processes involving A?.
