LRP‐1 Targeted Neuroprotection in a Mouse Model of Diabetic Retinopathy

Abstract

Human apolipoprotein E (apoE) is known to exert neuroprotective function in central nervous system disorders through low‐density lipoprotein receptor‐ related protein‐1 (LRP‐1). Retina being the same embryological origin like the brain, we rationale that retinal neurodegeneration can be inhibited by peptidomimetic blocking of LRP‐1. Thus, we predict a short peptide (apoEdp) mimicking the LRP‐1 binding region of apoE may have a role in the protection of retinal neuronal cells in the diabetic mouse eye model. Vascular changes in the retina are traditionally considered as classic diagnostic feature of Diabetic Retinopathy (DR). However, color blindness, lack of contrast sensitivity and abnormal electroretinogram characteristic to retinal neurodegeneration are documented in diabetic patients before clinically evident blood vessel changes. In fact, diabetes‐induced retinal neurodegeneration precedes vascular damage. Critical barriers to the development of adequate therapeutic strategies for the treatment of DR are related to the lack of information about the mechanism of early retinal neurodegeneration and its progression to late vascular abnormalities. Our studies with diabetic mouse retina suggest a signaling pathway involving low‐density lipoprotein receptor‐ related protein‐1 (LRP‐1) protects neurons from apoptosis by regulating the pro‐survival pathways of PI3k/Akt and MAPK/Erk pro‐survival pathway. We found apoEdp has anti‐PP2A activity in the diabetic retina and is effective in the treatment of retinal neurodegeneration in vivo. Our study suggests that intravitreal administration of apoEdp and its possible therapeutic neuroprotection will generate a proof of principle for treating diabetic neuronal complications.Support or Funding InformationSupport is provided in part by grant number 2G12MD007595‐06 from the National Institute on Minority Health and Health Disparities (NIMHD), National Institutes of Health (NIH), Department of Health and Human Services (DHHS) and its contents are solely the responsibility of the authors and do not necessarily represent the official views of NIMHD or NIH.