Tracking Down Glucosepane

The loss of physical function seen in aging tissues is partly due to the formation of irreversible crosslinks between proteins. A new paper in ACS Chemical Biology reports SRF-funded work in the lab of Yale's Prof. David Spiegel on an antibody that specifically labels the major crosslink glucosepane – a crucial step towards its removal.
spiegel_glucosepane_mab_th

Figure from Generation and Characterization of Anti-Glucosepane Antibodies Enabling Direct Detection of Glucosepane in Retinal Tissue.

The loss of physical function seen in aging tissues is partly due to the formation of irreversible crosslinks between proteins. A new paper in ACS Chemical Biology reports SRF-funded work in the lab of Yale’s Prof. David Spiegel on an antibody that specifically labels the major crosslink glucosepane – a crucial step towards its removal.

SRF launched the biotechnology company Revel Pharmaceuticals based on this work and previously published research on the synthesis of glucosepane.

Abstract

Although there is ample evidence that the advanced glycation end-product (AGE) glucosepane contributes to age-related morbidities and diabetic complications, the impact of glucosepane modifications on proteins has not been extensively explored due to the lack of sufficient analytical tools. Here, we report the development of the first polyclonal anti-glucosepane antibodies using a synthetic immunogen that contains the core bicyclic ring structure of glucosepane. We investigate the recognition properties of these antibodies through ELISAs involving an array of synthetic AGE derivatives and determine them to be both high-affinity and selective in binding glucosepane. We then employ these antibodies to image glucosepane in aging mouse retinae via immunohistochemistry. Our studies demonstrate for the first time accumulation of glucosepane within the retinal pigment epithelium, Bruch’s membrane, and choroid: all regions of the eye impacted by age-related macular degeneration. Co-localization studies further suggest that glucosepane colocalizes with lipofuscin, which has previously been associated with lysosomal dysfunction and has been implicated in the development of age-related macular degeneration, among other diseases. We believe that the anti-glucosepane antibodies described in this study will prove highly useful for examining the role of glycation in human health and disease.

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