April 2010
Volume 51, Issue 13
ARVO Annual Meeting Abstract  |   April 2010
Alzheimer’s Disease Amyloid-β Links Lens and Brain Pathology in Down Syndrome
Author Affiliations & Notes
  • J. A. Moncaster
    Psychiatry, Boston University, Boston, Massachusetts
  • R. D. Moir
    Neurology, Massachusetts General Hospital/Harvard Medical School, Charlestown, Massachusetts
  • R. Pineda, II
    Ophthalmology, Massachusetts Eye & Ear Infirmary, Boston, Massachusetts
  • J. G. Ghosh
    Psychiatry, Boston University, Boston, Massachusetts
  • R. M. Robb
    Ophthalmology, Childrens Hospital Boston/Harvard Medical School, Boston, Massachusetts
  • J. R. Kuszak
    Ophthalmology, Rush University Medical Center, Chicago, Illinois
  • J. I. Clark
    Biological Structure, University of Washington, Seattle, Washington
  • R. E. Tanzi
    Neurology, Massachusetts General Hospital/Harvard Medical School, Charlestown, Massachusetts
  • D. G. Hunter
    Ophthalmology, Childrens Hospital Boston, Boston, Massachusetts
  • L. E. Goldstein
    Psychiatry, Boston University, Boston, Massachusetts
  • Footnotes
    Commercial Relationships  J.A. Moncaster, None; R.D. Moir, None; R. Pineda, II, None; J.G. Ghosh, None; R.M. Robb, None; J.R. Kuszak, None; J.I. Clark, None; R.E. Tanzi, Neuroptix Corp., C; D.G. Hunter, None; L.E. Goldstein, Neuroptix Corp., C; Neuroptix Corp., P.
  • Footnotes
    Support  National Institute of General Medical Sciences (NIGMS) and National Institute of Aging (NIA), National Institutes of Health, Bethesda, MD; Cure for Alzheimer’s Fund, Anonymous Foundation.
Investigative Ophthalmology & Visual Science April 2010, Vol.51, 5804. doi:
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      J. A. Moncaster, R. D. Moir, R. Pineda, II, J. G. Ghosh, R. M. Robb, J. R. Kuszak, J. I. Clark, R. E. Tanzi, D. G. Hunter, L. E. Goldstein; Alzheimer’s Disease Amyloid-β Links Lens and Brain Pathology in Down Syndrome. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5804.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose: : Down syndrome (DS, trisomy 21) is the leading genetic cause of intellectual disability and the most common chromosomal disorder in humans. Chromosome 21 trisomy in DS leads to increased gene dosage of the APP gene (21q21) coding for the Alzheimer’s disease (AD) amyloid precursor protein (APP), increased expression of the APP amyloid-β (Aβ) cleavage peptides, accelerated cerebral Aβ accumulation, and invariant early-onset age-dependent AD neuropathology. The DS phenotype complex also includes high-penetrance expression of distinctive early-onset cerulean cataracts of unknown etiology. We previously reported pathogenic Aβ accumulation, co-localizing amyloid pathology, and disease-linked supranuclear cataracts in the lenses of subjects with AD. Here, we investigate the hypothesis that related AD-associated Aβ lens pathology is expressed as an age-dependent early-onset lens phenotype in DS.

Methods: : Ophthalmological examinations were correlated with phenotypic, histochemical, and biochemical analyses of lenses from subjects with DS, AD, and age-matched normal controls.

Results: : Lenses from subjects with DS demonstrated lenticular Aβ accumulation, cytosolic Aβ aggregate formation, co-localizing amyloid lens pathology, and distinctive supranuclear opacification identical to that previously identified in AD. Peptide sequencing, immunoblot analysis, and ELISA demonstrated accelerated age-dependent Aβ accumulation in the lenses of subjects with DS. Incubation of synthetic Aβ with human lens protein confirmed that this amyloidogenic peptide potently promotes lens protein aggregation and dose- and time-dependently increases Rayleigh light scattering.

Conclusions: : These results define the distinctive lens phenotype in DS as a genetic cataract and identify the molecular origin and pathogenic mechanism by which lens pathology is expressed in this common chromosomal disorder. Furthermore, these data establish age-dependent Aβ accumulation as the shared molecular etiology of disease-linked pathology in the lens and brain in both DS and AD.

Keywords: pathology: human • cataract • pathobiology 

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