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Sharon Bakalash, Michael Pham, Yosef Koronyo, Brenda C. Salumbides, Andrei Kramerov, Hillary Seidenberg, Dror Berel, Keith L. Black, Maya Koronyo-Hamaoui; Egr1 Expression Is Induced Following Glatiramer Acetate Immunotherapy in Rodent Models of Glaucoma and Alzheimer's Disease. Invest. Ophthalmol. Vis. Sci. 2011;52(12):9033-9046. doi: 10.1167/iovs.11-7498.
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Immunization with glatiramer acetate (GA) alleviates the neuropathology associated with glaucoma and Alzheimer's disease (AD) in rodent models. This research was undertaken to screen for molecular factors underlying GA-induced neuroprotective mechanisms in these models of chronic neurodegeneration.
Gene expression profiles were analyzed in GA-immunized versus nonimmunized elevated-intraocular pressure (IOP) rat models of glaucoma by using whole genome cDNA microarrays and were further validated by quantitative real-time PCR analysis. A gene, prominently upregulated by GA in elevated IOP retina, was further studied in APPSWE/PS1ΔE9-transgenic (AD-Tg) mice after GA immunization.
Seven days after treatment with GA, numerous genes were regulated in the retinas of rats with elevated IOP. Comprehensive functional classification and DAVID/KEGG enrichment analysis of GA-induced differentially expressed genes revealed annotation terms and pathways involved in neuroprotection, immune responses, cell communication, and regeneration. Specifically, increased mRNA levels of an early growth response (Egr) 1 gene were evident in GA-immunized retinas with elevated IOP. In AD-Tg mice, a significant increase in hippocampal EGR1 protein levels was also found in response to GA immunization. Nuclear EGR1 in the dentate gyrus colocalized more frequently with doublecortin-positive and Ki67 proliferating neural progenitors in GA-immunized as compared to nonimmunized AD-Tg mice. Further, EGR1 levels were negatively correlated with hippocampal amyloid-β plaque burden.
This study presents global gene expression profiles associated with GA immunization in a glaucoma rat model. Moreover, it identifies EGR1 transcription factor as a potential mediator for GA-induced neuroprotection in both glaucoma and AD.
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