Characterization and Non–Invasive Imaging of Lens ß–Amyloid in the Tg2576 Mouse Model of Alzheimer's Disease

Abstract

Abstract: : Purpose: Cerebral ß–amyloid (Aß) accumulation is a cardinal feature of Alzheimer's disease (AD). We have previously identified Aß deposition, amyloid pathology, and co–localizing supranuclear cataracts (SNC) in human AD lenses (Goldstein et al., Lancet, 2003). Similar lens pathology and Aß overexpression have been reported 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). In AD lens, Aß co–aggregates with alphaB–crystallin (and other cyoplasmic proteins) as e– dense cytosolic aggregates in supranuclear fiber cells. Similar molecular pathology may be detectable in vivo in Tg2576 mice. Methods: Immunohistochemistry/fluorescence, quantitative western blot, SELDI–MS, tryptic digest/MS sequencing, immunogold EM, EM autometallography; stereophotomicroscopy. Non–invasive in vivo techniques: static and quasi–elastic light scattering (SLS,QLS), fluorescent ligand scanning (FLS). Results: Human Aß/ß–APP are overexpressed in Tg2576 mouse lens. Cytosolic e– dense Aß aggregates are present in Tg2576 but not WT fiber cells. Tg2576 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). Systemic administration of a fluorescent lipophilic amyloid–binding ligand (Me–X04, Klunk et al. J Neuropathol Exp Neurol [2002] 61:797) in Tg2576 and amyloid–bearing 87V Prp–infected mice resulted in supranuclear Me–X04 binding in vivo. Supranuclear Me–X04 histofluorescence, Aß immunostaining, and amyloid pathology were also observed in ex vivo lens specimens. Preliminary results suggest that Aß pathology may be present and detectable earlier in lens than in brain. Conclusions: Tg2576 mice express human Aß in the lens and exhibit SNC pathology. Tg2576 mice afford an ideal animal model for non–invasive detection and quantitative in vivo monitoring of Aß–associated lens pathology.

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