Ab in Lens in Down Syndrome Figure 9. Model pathogenic pathways in Down syndrome brain and lens. Triplication of human chromosome 21 in Down syndrome results in increased dosage of the APP gene (21q21), overexpression of the Alzheimer’s disease amyloid-b precursor protein (APP), and progressive accumulation of amyloidogenic amyloid-b peptides (Ab) in the brain and lens. Deposition of Ab in both anatomical compartments results in age- dependent Ab amyloid pathology and disease-linked tissue-specific phenotypes in both Down syndrome and Alzheimer’s disease. See text for details. doi:10.1371/journal.pone.0010659.g009 The significance and natural history of variability in Ab tissue concentration in the lens and its possible relationship to the brain in DS are subjects of ongoing investigation. In this study, we identify Ab amyloid pathology as the shared molecular etiology of two defining features of DS, namely, supranuclear cataracts in the lens and AD neuropathology in the brain. The proximal pathogenesis of both pathologies likely derives from the primary chromosomal disorder and associated APP gene- dosage imbalance (Fig. 9). The results reported here support a testable pathogenic mechanism by which the primary chromosomal disorder in DS may be translated into a distinctive phenotype expressed in the lens. In this regard, the phenotypic concordance of Ab lens pathology in both diseases, DS and AD, is striking. Given that DS-linked pathology may be indicative of aberrant Ab accumulation in both compartments, the lens may provide an optically accessible target tissue for early detection and longitudinal assessment of early Ab molecular pathology in DS and AD. Future clinical studies will be required to systematically evaluate the frequency of this supranuclear phenotype in DS patients. Quasi- elastic light scattering instrumentation or other techniques may provide a practical approach for quantitative assessment of specific lens pathology throughout the course of the disease. Supporting Information Figure S1 Stereo image pair demonstrating mature supranucle- ar pathology in the lens (with intact zonule fibers) from a subject with Down syndrome. Characteristic circumferential supranuclear References cataract in the lens of a 64-year-old male subject with Down syndrome. This distinctive cataract is evident as an annular half- toroid band of opacification in the deep cortical and supranuclear subregions of the lens (shown with intact zonules). This same lens specimen is presented as a slit lamp image (Fig. 1H) and as a stereo image pair (without zonules, Fig. 2A). This dramatic Down syndrome cataract is phenotypically comparable to the subequa- torial supranuclear cataract observed in advanced Alzheimer’s disease. These distinctive supranuclear cataracts are not observed in age-normal control subjects. See text for details. Found at: doi:10.1371/journal.pone.0010659.s001 (2.77 MB TIF) Acknowledgments We thank Mr. Joseph Bertelsen (Signet Laboratories, Covance, Dedham, MA) for generously providing 6E10 and 4G8 monoclonal antibodies. We gratefully acknowledge the National Disease Registry Interchange, Sun Health Research Institute, and the Florida Lion’s Eye Bank for their assistance with tissue procurement. We would like to thank the many patients and families who made this work possible. Author Contributions Conceived and designed the experiments: JAM RP RDM RMR JIC RET DGH LEG. Performed the experiments: JAM RDM SL MAB JGG ME SJS AM. Analyzed the data: JAM RP RDM MAB ME JK JIC RET DGH LEG. Contributed reagents/materials/analysis tools: JAM RP RDM SL MAB ME RF RMR JK RET DGH LEG. Wrote the paper: JAM RP RDM DGH LEG. Revised the manuscript: JGG AM RF RMR JK JIC RET. 1. Down JLH (1866) Observations on an ethnic classification of idiots. London Hosp Clin Lect Rep 3: 259. 2. Epstein CJ (1989) Down syndrome, trisomy 21. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. Metabolic Basis of Inherited Disease. New York: McGraw-Hill. pp 291–326. 3. Online Mendelian Inheritance in Man - Down Syndrome. Available: http://www. ncbi.nlm.nih.gov/entrez/dispomim.cgi?id = 190685. Accessed 25 April 2010. 4. Pueschel SM (1990) Clinical aspects of Down syndrome from infancy to adulthood. Am J Med Genet Suppl 7: 52–56. 5. Roizen NJ, Patterson D (2003) Down’s syndrome. The Lancet 361: 1281–1289. PLoS ONE | www.plosone.org 12 May 2010 | Volume 5 | Issue 5 | e10659