Non–Invasive Molecular Imaging of Alzheimer’s Disease ß–Amyloid and Scrapieform Prion Protein (Prpsc) in the Lens

Abstract

Purpose: : We have previously identified Aß deposition, amyloid pathology, and co–localizing supranuclear cataracts (SNC) in human AD lenses (Goldstein et al., Lancet, 2003) and in Tg2576 mice (Goldstein et al. [2001] 42: ARVO Abst 1614; Render et al. [2003] 44: ARVO Abst 3063), an established AD mouse model (Hsiao, Science [1996] 274:99). Here we investigate amyloid deposition in ß–amyloid overexpressing transgenic mice and scrapiform prion protein (PrP^sc)–infected sheep and mice.

Methods: : Immunohistochemistry/fluorescence, quantitative western blot, SELDI–MS, tryptic digest/MS sequencing, immunogold EM; stereophotomicroscopy. Non–invasive in vivo techniques: static and quasi–elastic light scattering (SLS,QLS).

Results: : We confirm our previously reported ß–amyloid lens pathology in transgenic mice. We demonstrate proteinase K resistant prion protein in the lenses of confirmed PrP^sc infected sheep and PrP^sc (87v) inoculated mice. Inoculated mice showed morphologically variable SNC phenotypic expression. Non–invasive quantitative in vivo lens analyses were accomplished using static light scattering (SLS, Seeberger et al., J Biomed Opt. [2004] 9:116) and a more sensitive quantitative technique, quasi–elastic light scattering (QLS, Optiscan 1300, Neuroptix, Amherst, MA), both utilized in non–anesthetized animals. Systemic administration of a fluorescent lipophilic amyloid–binding ligand (Me–X04, Klunk et al. J Neuropathol Exp Neurol [2002] 61:797) in 87v PrP^sc–inoculated mice resulted in supranuclear Me–X04 binding in vivo. Supranuclear Me–X04 histofluorescence, PrP immunostaining, and amyloid pathology were also observed in ex vivo lens specimens. Preliminary results suggest that PrP^sc –related amyloid pathology can be detected non–invasively in the lens.

Conclusions: : Alzheimer's and PrP^sc–related amyloid pathology is detectable in the lens in various species.

Keywords: cataract • imaging/image analysis: non-clinical • pathology: experimental