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    The Impact of APP on Alzheimer-like Pathogenesis and Gene Expression in Down Syndrome iPSC-Derived Neurons

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    Author
    Ovchinnikov, DA; Korn, O; Virshup, I; Wells, CA; Wolvetang, EJ
    Date
    2018-07-10
    Source Title
    Stem Cell Reports
    Publisher
    CELL PRESS
    University of Melbourne Author/s
    Wells, Christine; Virshup, Isaac
    Affiliation
    Anatomy and Neuroscience
    Metadata
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    Document Type
    Journal Article
    Citations
    Ovchinnikov, D. A., Korn, O., Virshup, I., Wells, C. A. & Wolvetang, E. J. (2018). The Impact of APP on Alzheimer-like Pathogenesis and Gene Expression in Down Syndrome iPSC-Derived Neurons. STEM CELL REPORTS, 11 (1), pp.32-42. https://doi.org/10.1016/j.stemcr.2018.05.004.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/255197
    DOI
    10.1016/j.stemcr.2018.05.004
    Abstract
    Early-onset Alzheimer disease (AD)-like pathology in Down syndrome is commonly attributed to an increased dosage of the amyloid precursor protein (APP) gene. To test this in an isogenic human model, we deleted the supernumerary copy of the APP gene in trisomic Down syndrome induced pluripotent stem cells or upregulated APP expression in euploid human pluripotent stem cells using CRISPRa. Cortical neuronal differentiation shows that an increased APP gene dosage is responsible for increased β-amyloid production, altered Aβ42/40 ratio, and deposition of the pyroglutamate (E3)-containing amyloid aggregates, but not for several tau-related AD phenotypes or increased apoptosis. Transcriptome comparisons demonstrate that APP has a widespread and temporally modulated impact on neuronal gene expression. Collectively, these data reveal an important role for APP in the amyloidogenic aspects of AD but challenge the idea that increased APP levels are solely responsible for increasing specific phosphorylated forms of tau or enhanced neuronal cell death in Down syndrome-associated AD pathogenesis.

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