Transcriptomics,Genomics

Dataset Information

48

APP levels mediate beta-amyloid but not tau-related aspects of Alzheimer’s disease in a Down syndrome model of cortical neurogenesis.


ABSTRACT: Early-onset Alzheimer’s disease-like pathology in Down syndrome (DS, trisomy 21) is commonly attributed to an increased dosage of the amyloid precursor protein (APP) gene. To test this central tenet of the amyloid-cascade hypothesis we deleted the supernumerary copy of the APP gene in trisomic DS iPSC, or upregulated APP expression in euploid human pluripotent stem cell lines with dCas9-VP64, and subjected these lines to prolonged cortical neural differentiation. Our data reveal that increased APP gene dosage and expression is necessary and sufficient for increased beta-amyloid production and pyroglutamate(E3)-containing plaque deposition, but is neither sufficient nor required for tau hyperphosphorylation, neurofibrillary tangle formation, or increased oxidative stress-induced apoptosis in neurons. Transcriptome comparisons of the isogenic neurons demonstrates that the supernumerary APP gene copy has profound temporally-modulated genome-wide effects on gene expression during differentiation and maturation of DS neuronal cultures that link APP function to regulation of genes involved in neuronal synaptic function and outgrowth of neuronal processes. Collectively, our data reveal that APP plays an important role in the amyloidogenic aspects of Alzheimer’s disease, but challenge the hypothesis that increased APP levels are solely responsible for hyperphosphorylation of tau or enhanced oxidative stress-induced neuronal cell death in Down syndrome associated AD-pathogenesis. Overall design: 34 samples

INSTRUMENT(S): Illumina HumanHT-12 V4.0 expression beadchip

SUBMITTER: Tyrone Chen  

PROVIDER: GSE100680 | GEO | 2018-06-12

REPOSITORIES: GEO

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Publications

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

Ovchinnikov Dmitry A DA   Korn Othmar O   Virshup Isaac I   Wells Christine A CA   Wolvetang Ernst J EJ  

Stem cell reports 20180531 1


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-amyl  ...[more]

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