Ab in Lens in Down Syndrome Figure 8. Age-dependent supranuclear cataractogenesis in Down syndrome. The anatomical localization of the characteristic Down syndrome cataract phenotype (white shading) reflects the temporal origin and natural history of the underlying lens pathology. Fetal lens fiber cells are not involved in this pathogenic process. Parentheses indicate equatorial axial extent of age-dependent disease-linked Abpathology in the supranuclear subregion of Down syndrome lenses. See text for details. doi:10.1371/journal.pone.0010659.g008 nitive sequelae. With respect to the lens, the present investigation supports the hypothesis that increased expression of Ab in the lens leads to amyloidogenic interactions with other structural proteins (e.g., aB-crystallin) within the cytoplasm of supranuclear lens fiber cells. This pathogenic cascade leads to increased lens protein aggregation, light scattering, opacification, and ultimately, disease-linked cataracts [45]. Given the fact that the long-lived lens fiber cells are metabolically sluggish and demonstrate limited capacity to catabolize aggregated protein, we speculate that DS-linked Ab amyloid pathology in the lens may precede corresponding Ab pathology in the brain. Regardless, the proposed pathogenic model for Ab pathology in both tissue compartments (brain and lens) is in general agreement with a broad conception of the amyloid cascade hypothesis [16,46,47]. We hypothesize that the Ab detected in DS lenses is generated endogenously. The human lens expresses the full complement of enzymes and precursor proteins necessary to generate and process Ab [28,48,49,50]. In the present study, this hypothesis is supported by the finding of intense Ab immunoreactivity in DS lens epithelial cells. Our finding that lens fiber cell Ab is exclusively cytoplasmic suggests that this amyloidogenic peptide may be released from intracellular processing compartments during organelle disintegration accompa- nying epithelial-to-fiber cell terminal differentiation. This model points to the lens as an appropriate target for ascertaining the temporal origin and natural history of AD-linked molecular pathology in vivo. Our findings suggest an apparent temporal discordance in DS with respect to phenotype expression in the lens and brain, with pathology in the former preceding that in the latter. However, we also observed variability in age-dependent phenotypic expression of Ab molecular pathology in the lens that comports with analogous variability in the brain of subjects with DS [34,51]. PLoS ONE | www.plosone.org 11 May 2010 | Volume 5 | Issue 5 | e10659