Alzheimer’s Disease Amyloid-b Links Lens and Brain Pathology in Down Syndrome Juliet A. Moncaster1., Roberto Pineda2., Robert D. Moir3., Suqian Lu 1 , Mark A. Burton1, Joy G. Ghosh1, Maria Ericsson4, Stephanie J. Soscia3, Anca Mocofanescu1, Rebecca D. Folkerth5, Richard M. Robb6, Jer R. Kuszak7, John I. Clark8, Rudolph E. Tanzi3, David G. Hunter6, Lee E. Goldstein1* 1 Molecular Aging & Development Laboratory, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America, 2 Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, United States of America, 3 Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, United States of America, 4 Electron Microscopy Facility, Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, United States of America, 5 Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America, 6 Department of Ophthalmology, Children’s Hospital Boston, Harvard Medical School, Boston, Massachusetts, United States of America, 7 Departments of Ophthalmology and Pathology, Rush University Medical Center, Chicago, Illinois, United States of America, 8 Departments of Biological Structure and Ophthalmology, University of Washington, Seattle, Washington, United States of America Abstract Down syndrome (DS, trisomy 21) is the most common chromosomal disorder and the leading genetic cause of intellectual disability in humans. In DS, triplication of chromosome 21 invariably includes the APP gene (21q21) encoding the Alzheimer’s disease (AD) amyloid precursor protein (APP). Triplication of the APP gene accelerates APP expression leading to cerebral accumulation of APP-derived amyloid-b peptides (Ab), early-onset AD neuropathology, and age-dependent cognitive sequelae. The DS phenotype complex also includes distinctive early-onset cerulean cataracts of unknown etiology. Previously, we reported increased Ab accumulation, co-localizing amyloid pathology, and disease-linked supranuclear cataracts in the ocular lenses of subjects with AD. Here, we investigate the hypothesis that related AD-linked Ab pathology underlies the distinctive lens phenotype associated with DS. Ophthalmological examinations of DS subjects were correlated with phenotypic, histochemical, and biochemical analyses of lenses obtained from DS, AD, and normal control subjects. Evaluation of DS lenses revealed a characteristic pattern of supranuclear opacification accompanied by accelerated supranuclear Ab accumulation, co-localizing amyloid pathology, and fiber cell cytoplasmic Ab aggregates (,5 to 50 nm) identical to the lens pathology identified in AD. Peptide sequencing, immunoblot analysis, and ELISA confirmed the identity and increased accumulation of Ab in DS lenses. Incubation of synthetic Ab with human lens protein promoted protein aggregation, amyloid formation, and light scattering that recapitulated the molecular pathology and clinical features observed in DS lenses. These results establish the genetic etiology of the distinctive lens phenotype in DS and identify the molecular origin and pathogenic mechanism by which lens pathology is expressed in this common chromosomal disorder. Moreover, these findings confirm increased Ab accumulation as a key pathogenic determinant linking lens and brain pathology in both DS and AD. Citation: Moncaster JA, Pineda R, Moir RD, Lu S, Burton MA, et al. (2010) Alzheimer’s Disease Amyloid-b Links Lens and Brain Pathology in Down Syndrome. PLoS ONE 5(5): e10659. doi:10.1371/journal.pone.0010659 Editor: Leonard Petrucelli, Mayo Clinic, United States of America Received December 3, 2009; Accepted April 20, 2010; Published May 20, 2010 Copyright: 2010 Moncaster et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: National Institutes of Health, Bethesda, MD (R01GM75986 and K23AG024792, LEG); American Federation for Aging Research, New York, NY (LEG); Alzheimer’s Association, Chicago, IL (LEG); American Health Assistance Foundation, Clarksburg, MD (LEG); Anonymous Foundation (LEG); Cure Alzheimer’s Fund, Wellesley Hills, MA (RDM); Boston University School of Medicine, Boston, MA (LEG); and Boston University Alzheimer’s Disease Center, Boston, MA (NIH ADCC grant P30AG13846). The funding sponsors had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The senior corresponding author (LEG) has full access to all study data and takes final responsibility for the decision to submit the results of the study for publication. Competing Interests: Authors Moncaster, Pineda, Lu, Burton, Ghosh, Ericsson, Soscia, Mocofanescu, Folkerth, Robb, Kuszak, Clark, and Hunter report no conflict of interest. The following authors reported consultant activity during the course of this study: Drs. Tanzi and Goldstein, Neuroptix Corp, Acton, MA; Drs. Moir, Tanzi, and Goldstein, Covance, Dedham, MA. No financial support was provided by any commercial entity for this study. * E-mail: LGOLD@BU.EDU . These authors contributed equally to this work. Introduction Down syndrome (DS, [1]) is the leading genetic cause of intellectual disability and the most common chromosomal disorder compatible with human survival [2,3,4,5]. DS affects approxi- mately 1 in 700 live births and an estimated 220,000 newborns each year [6]. In the majority of cases, the disorder arises from sporadic non-disjunction of chromosome 21 (HSA21) and triplication of the entire chromosome [7,8,9], or infrequently, from partial aneuploidy due to unbalanced chromosomal translocation [10,11,12,13]. In most cases, DS aneuploidy disrupts gene-dose equilibrium in all somatic cells, whereas a minority of cases demonstrates mosaicism [14]. Chromosomal triplication invariably includes the APP gene (21q21) that encodes the amyloid precursor protein, APP [15,16]. Endoproteolytic cleavage of APP yields the pathogenic amyloid-b peptides (Ab) that progressively accumulate in the brain as the diffuse and neuritic plaques of Alzheimer’s disease (AD). In DS, cerebral Ab accumulation is PLoS ONE | www.plosone.org 1 May 2010 | Volume 5 | Issue 5 | e10659