PEDF-derived peptide protects against Amyloid-β toxicity in vitro and prevents retinal dysfunction in rats.

Abstract

Purpose : Amyloid-beta (Aβ), a family of aggregation-prone polypeptides, has been found as a significant constituent of drusen, thus implicated in the pathophysiology of age-related macular degeneration (AMD). We have shown that well-defined Aβ species possess differential retinal neurotoxicity in rats, where fibrillar and oligomeric assemblies of the Aβ42 isoform stood as the primary retinotoxic entities. Previous studies showed that Aβ binding to the 67kDa laminin receptor (67LR) leads to the internalization and amyloid-related neuronal cell death. Anti-67LR has been used to treat models of Alzheimer’s disease, thus supporting the role of this receptor in Aβ pathways. We have found that PEDF335, a pigment epithelium-derived factor (PEDF)-derived peptide, can bind to 67LR. Here, we hypothesized that PEDF335 may limit internalization of Aβ, thereby ameliorating its retinal toxicity in vivo.

Methods : Neuroscreen-1 (NS-1) cells were cultured with PEDF335 for 1 h before treatment with oligomeric Aβ25-35 or Aβ42 for 24 h. Cell viability was determined by MTT assay. Fluorescent PEDF335 uptake into the cells was assessed.
Wild type rats were treated with intravitreal administration (10µl) of PEDF335 (3mM) in each eye three days prior to injection of oligomeric or fibrillary Aβ42 assemblies to the right eye. Retinal function was assessed at baseline and thereafter at 3, 7 and 14 days after the injection. At each time point, electroretinography (ERG) measures were compared between eyes.

Results : PEDF335 treatment blocked amyloid endocytosis and protected NS-1 cells from Aβ42-induced apoptosis in vitro. We then observed in vivo protection by PEDF335 against Aβ42-mediated retinal dysfunction. In the presence of PEDF335, ERG responses in rat eyes treated with fibrillary Aβ42 were intact, whereas those measured in eyes treated with oligomeric Aβ42 showed marginal attenuation through 14 days. No retinal compromise was recorded in response to PEDF335.

Conclusions : Our results provide conceptual evidence that PEDF335 protects against oligomeric and fibrillary Aβ42 retinal toxicity, at least in part, via binding to 67LR through prion protein and inhibition of internalization of the assemblies. Such insights may promote the mechanistic understanding of the pathogenicity of particular Aβ species, and may merit further investigation as a potential strategy in AMD.

This is a 2020 ARVO Annual Meeting abstract.