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Differential effects of amyloid-beta peptide aggregation status on in vivo retinal neurotoxicity

Authors Watts E, Anderson P, Ma D, Philpott K, Jen S, Croucher M, Jen L, Gentleman S

Published 30 August 2010 Volume 2010:2 Pages 121—137

DOI https://doi.org/10.2147/EB.S9902

Review by Single-blind

Peer reviewer comments 3


HR Watts1, PJB Anderson1, D Ma2, KL Philpott3, SM Jen1, M Croucher1, LS Jen1, SM Gentleman1

1Department of Medicine, Imperial College London, Charing Cross Campus, London, UK; 2Department of Surgery and Cancer, Imperial College London, Chelsea and Westminster Hospital, London, UK; 3Neurosciences, Centre of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, Harlow, Essex, UK; HR Watts and PJB Anderson contributed equally to this paper

Abstract: The present study examined the relationship between amyloid beta (Aβ)-peptide aggregation state and neurotoxicity in vivo using the rat retinal–vitreal model. Following single unilateral intravitreal injection of either soluble Aβ1–42 or Aβ1–42 preaggregated for different ­periods, retinal pathology was evaluated at 24 hours, 48 hours, and 1-month postinjection. Injection of either soluble Aβ (sAβ) or preaggregated Aβ induced a rapid reduction in ­immunoreactivity (IR) for synaptophysin, suggesting that direct contact with neurons is not necessary to disrupt synapses. Acute neuronal ionic and metabolic dysfunction was demonstrated by widespread loss of IR to the calcium buffering protein parvalbumin (PV) and protein gene product 9.5, a component of the ubiquitin-proteosome system. Injection of sAβ appeared to have a more rapid impact on PV than the preaggregated treatments, producing a marked reduction in PV cell diameters at 48 hours, an effect that was only observed for preaggregated Aβ after 1-month survival. Extending the preaggregation period from 4 to 8 days to obtain highly fibrillar Aβ species significantly increased the loss of choline acteyltransferase IR, but had no effect on PV-IR. These findings prompt the conclusion that Aβ assembly state has a significant impact on in vivo neurotoxicity by triggering distinct molecular changes within the cell.

Keywords: Alzheimer disease, retina

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