title: Alzheimer's disease amyloid-beta links lens and brain pathology in Down syndrome.
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-beta peptides (Abeta), 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 Abeta 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 Abeta 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 Abeta accumulation, co-localizing amyloid pathology, and fiber cell cytoplasmic Abeta aggregates (approximately 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 Abeta in DS lenses. Incubation of synthetic Abeta 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 Abeta accumulation as a key pathogenic determinant linking lens and brain pathology in both DS and AD.
authors.affiliation: Molecular Aging & Development Laboratory, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Juliet A
authors.initials: JA
authors.lastname: Moncaster
authors.forename: Roberto
authors.initials: R
authors.lastname: Pineda
authors.forename: Robert D
authors.initials: RD
authors.lastname: Moir
authors.forename: Suqian
authors.initials: S
authors.lastname: Lu
authors.forename: Mark A
authors.initials: MA
authors.lastname: Burton
authors.forename: Joy G
authors.initials: JG
authors.lastname: Ghosh
authors.forename: Maria
authors.initials: M
authors.lastname: Ericsson
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Soscia
authors.forename: Anca
authors.initials: A
authors.lastname: Mocofanescu
authors.forename: Rebecca D
authors.initials: RD
authors.lastname: Folkerth
authors.forename: Richard M
authors.initials: RM
authors.lastname: Robb
authors.forename: Jer R
authors.initials: JR
authors.lastname: Kuszak
authors.forename: John I
authors.initials: JI
authors.lastname: Clark
authors.forename: Rudolph E
authors.initials: RE
authors.lastname: Tanzi
authors.forename: David G
authors.initials: DG
authors.lastname: Hunter
authors.forename: Lee E
authors.initials: LE
authors.lastname: Goldstein
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism / Q000473:pathology; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D001921:Brain / Q000473:pathology* / Q000648:ultrastructure; D002386:Cataract / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D004314:Down Syndrome / Q000378:metabolism / Q000473:pathology*; D005136:Eye Proteins / Q000737:chemistry / Q000378:metabolism; D005260:Female; D006801:Humans; D007908:Lens, Crystalline / Q000473:pathology* / Q000648:ultrastructure; D008027:Light; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020836:Protein Structure, Quaternary; D012542:Scattering, Radiation; D055815:Young Adult
chemical_list: D016229:Amyloid beta-Peptides; D005136:Eye Proteins