Glial and endothelial blood-retinal barrier responses to amyloid-β in the neural retina of the rat

Peter JB Anderson^1,a, HR Watts^1,a, CJ Hille³, KL Philpott³, P Clark⁴, M Croucher, S Gentleman², Ling-Sun Jen¹

¹Department of Cellular and Molecular Neuroscience; ²Department of Clinical Neuroscience, Division of Neuroscience and Mental Health, Imperial College London, Charing Cross Hospital Campus, London, UK; ³Neurosciences, Centre of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, Harlow, Essex, UK; ⁴Leukocyte Biology Section, National Heart and Lung Institute, Imperial College London, London, UK; ^aThese researchers contributed equally to this paper

Abstract: The effects of an intravitreal or subretinal injection of soluble or aggregated forms of Aβ_1–42 on retinal nestin-immunoreactivity (-IR) and glial fibrillary acidic protein (GFAP)-IR in astrocytes and Müller glial cells and the integrity of the blood-retinal barrier (BRB) were tested in the in vivo rat vitreal-retinal model. Retinas were exposed for 1, 2, 3, 5 or 30 days. We present novel data demonstrating that aggregated Aβ_1–42 up-regulates nestin-IR in astrocytes and Müller cells, with a graded response directly related to the length of pre-injection aggregation time. Similar results were obtained with GFAP-IR, but the signal was weaker. An intravitreal injection of aggregated Aβ_1–42 led to VEGF-IR up-regulation, particularly in the GCL and to a lesser extent in the INL. VEGFR1-IR (Flt1) was also increased, particularly in Müller cells and this was accompanied by marked leakage of albumin into the retinal parenchyma of the injected eye, but not in the contralateral eye.

Keywords: amyloid-β, Müller cells, blood-retinal barrier