Non-amyloidogenic effects of α2 adrenergic agonists: implications for brimonidine-mediated neuroprotection

The amyloid beta (Aβ) pathway is strongly implicated in neurodegenerative conditions such as Alzheimer’s disease and more recently, glaucoma. Here, we identify theα2 adrenergic receptor agonists (α2ARA) used to lower intraocular pressure can prevent retinal ganglion cell (RGC) death via the non-amyloidogenic Aβ-pathway. Neuroprotective effects were confirmedin vivoandin vitroin different glaucoma-related models usingα2ARAs brimonidine (BMD), clonidine (Clo) and dexmedetomidine.α2ARA 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 Aβ-induced neurotoxicity model (67% BMD and 88.6% Clo, bothP<0.01, respectively), andin vitro, whereα2ARAs 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 Aβand amyloid precursor protein (APP) levels at 3 and 8 weeks, respectively, in the RGC layer, with similar results with Clo, andin vitrowith all threeα2ARAs. BMD significantly increased soluble APPα(sAPPα) levels at 3 and 8 weeks (2.1 and 1.6-fold)in vivoandin vitrowith the CoCl2and UV-light insults. Furthermore, treatment of UV-insulted cells with an sAPPαantibody significantly reduced cell viability compared with BMD-treated control (52%), co-treatment (33%) and untreated control (27%). Finally, we show thatα2ARAs modulate levels of laminin and MMP-9 in RGCs, potentially linked to changes in Aβthrough APP processing. Together, these results provide new evidence thatα2ARAs are neuroprotective through their effects on the Aβpathway and sAPPα, which to our knowledge, is the first description. Studies have identified the need forα-secretase activators and sAPPα-mimetics in neurodegeneration;α2ARAs, already clinically available, present a promising therapy, with applications not only to reducing RGC death in glaucoma but also other neurodegenerative processes involving Aβ.