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Here, we identify the<jats:italic>\u03b1<\/jats:italic>2 adrenergic receptor agonists (<jats:italic>\u03b1<\/jats:italic>2ARA) used to lower intraocular pressure can prevent retinal ganglion cell (RGC) death via the non-amyloidogenic A<jats:italic>\u03b2<\/jats:italic>-pathway. Neuroprotective effects were confirmed<jats:italic>in vivo<\/jats:italic>and<jats:italic>in vitro<\/jats:italic>in different glaucoma-related models using<jats:italic>\u03b1<\/jats:italic>2ARAs brimonidine (BMD), clonidine (Clo) and dexmedetomidine.<jats:italic>\u03b1<\/jats:italic>2ARA treatment significantly reduced RGC apoptosis in experimental-glaucoma models by 97.7% and 92.8% (BMD,<jats:italic>P<\/jats:italic>&lt;0.01) and 98% and 92.3% (Clo,<jats:italic>P<\/jats:italic>&lt;0.01)) at 3 and 8 weeks, respectively. A reduction was seen in an experimental A<jats:italic>\u03b2<\/jats:italic>-induced neurotoxicity model (67% BMD and 88.6% Clo, both<jats:italic>P<\/jats:italic>&lt;0.01, respectively), and<jats:italic>in vitro<\/jats:italic>, where<jats:italic>\u03b1<\/jats:italic>2ARAs significantly (<jats:italic>P<\/jats:italic>&lt;0.05) prevented cell death, under both hypoxic (CoCl<jats:sub>2<\/jats:sub>) and stress (UV) conditions. In experimental-glaucoma, BMD induced ninefold and 25-fold and 36-fold and fourfold reductions in A<jats:italic>\u03b2<\/jats:italic>and amyloid precursor protein (APP) levels at 3 and 8 weeks, respectively, in the RGC layer, with similar results with Clo, and<jats:italic>in vitro<\/jats:italic>with all three<jats:italic>\u03b1<\/jats:italic>2ARAs. BMD significantly increased soluble APP<jats:italic>\u03b1<\/jats:italic>(sAPP<jats:italic>\u03b1<\/jats:italic>) levels at 3 and 8 weeks (2.1 and 1.6-fold)<jats:italic>in vivo<\/jats:italic>and<jats:italic>in vitro<\/jats:italic>with the CoCl<jats:sub>2<\/jats:sub>and UV-light insults. Furthermore, treatment of UV-insulted cells with an sAPP<jats:italic>\u03b1<\/jats:italic>antibody significantly reduced cell viability compared with BMD-treated control (52%), co-treatment (33%) and untreated control (27%). Finally, we show that<jats:italic>\u03b1<\/jats:italic>2ARAs modulate levels of laminin and MMP-9 in RGCs, potentially linked to changes in A<jats:italic>\u03b2<\/jats:italic>through APP processing. Together, these results provide new evidence that<jats:italic>\u03b1<\/jats:italic>2ARAs are neuroprotective through their effects on the A<jats:italic>\u03b2<\/jats:italic>pathway and sAPP<jats:italic>\u03b1<\/jats:italic>, which to our knowledge, is the first description. Studies have identified the need for<jats:italic>\u03b1<\/jats:italic>-secretase activators and sAPP<jats:italic>\u03b1<\/jats:italic>-mimetics in neurodegeneration;<jats:italic>\u03b1<\/jats:italic>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<jats:italic>\u03b2<\/jats:italic>.<\/jats:p>","DOI":"10.1038\/cddis.2016.397","type":"journal-article","created":{"date-parts":[[2016,12,8]],"date-time":"2016-12-08T13:45:58Z","timestamp":1481204758000},"page":"e2514-e2514","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":67,"title":["Non-amyloidogenic effects of \u03b12 adrenergic agonists: implications for brimonidine-mediated neuroprotection"],"prefix":"10.1038","volume":"7","author":[{"given":"Shereen","family":"Nizari","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin M","family":"Davis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo M","family":"Normando","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joana","family":"Galvao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa A","family":"Turner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mukhtar","family":"Bizrah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad","family":"Dehabadi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kailin","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M Francesca","family":"Cordeiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,12,8]]},"reference":[{"key":"BFcddis2016397_CR1","doi-asserted-by":"publisher","first-page":"13352","DOI":"10.1073\/pnas.0405479101","volume":"101","author":"MF Cordeiro","year":"2004","unstructured":"Cordeiro MF, Guo L, Luong V, Harding G, Wang W, Jones HE et al. 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