Dataset Information

Down syndrome, beta-amyloid and neuroimaging.

ABSTRACT: This review focuses on the role of A? in AD pathogenesis in Down syndrome and current approaches for imaging A? in vivo. We will describe how A? deposits with age, the posttranslational modifications that can occur, and detection in biofluids. Three unique case studies describing partial trisomy 21 cases without APP triplication, and the occurrences of low level mosaic trisomy 21 in an early onset AD patient are presented. Brain imaging for A? includes those by positron emission tomography and ligands (Pittsburgh Compound B, Florbetapir, and FDDNP) that bind A? have been published and are summarized here. In combination, we have learned a great deal about A? in DS in terms of characterizing age of onset of this pathology and it is exciting to note that there is a clinical trial in DS targeting A? that may lead to clinical benefits.

SUBMITTER: Head E

PROVIDER: S-EPMC5748259 | biostudies-other | 2018 Jan

REPOSITORIES: biostudies-other

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Down syndrome, beta-amyloid and neuroimaging.

Head Elizabeth E Helman Alex M AM Powell David D Schmitt Frederick A FA

Free radical biology & medicine 20170919

This review focuses on the role of Aβ in AD pathogenesis in Down syndrome and current approaches for imaging Aβ in vivo. We will describe how Aβ deposits with age, the posttranslational modifications that can occur, and detection in biofluids. Three unique case studies describing partial trisomy 21 cases without APP triplication, and the occurrences of low level mosaic trisomy 21 in an early onset AD patient are presented. Brain imaging for Aβ includes those by positron emission tomography and l ...[more]

PMID: 28935420

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Project description: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.

Dataset Information

Down syndrome, beta-amyloid and neuroimaging.

Publications

Down syndrome, beta-amyloid and neuroimaging.

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