The Impact of APP on Alzheimer-like Pathogenesis and Gene Expression in Down Syndrome iPSC-Derived Neurons
Summary: 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 pluripot...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2018-07-01
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| Series: | Stem Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213671118302212 |
| _version_ | 1818519986577080320 |
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| author | Dmitry A. Ovchinnikov Othmar Korn Isaac Virshup Christine A. Wells Ernst J. Wolvetang |
| author_facet | Dmitry A. Ovchinnikov Othmar Korn Isaac Virshup Christine A. Wells Ernst J. Wolvetang |
| author_sort | Dmitry A. Ovchinnikov |
| collection | DOAJ |
| description | Summary: 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. : Wolvetang and colleagues used CRISPR/Cas9 technologies to manipulate the copy number and expression of the amyloid precursor protein (APP) gene in Down syndrome and corresponding euploid pluripotent stem cells. They demonstrate that APP modulates the expression of a surprisingly large cohort of genes and dictates Aβ42/40 ratio and pyroglutamate-E3 foci but does not affect hyperphosphorylated forms of tau associated with Alzheimer disease or neuronal cell death of in vitro generated cortical neurons. Keywords: beta-amyloid, iPSC, Down syndrome, Hsa21 trisomy, CRISPR/Cas9, cortical neurogenesis, gene expression profiling, tau phosphorylation |
| first_indexed | 2024-12-11T01:31:21Z |
| format | Article |
| id | doaj.art-11f162d4b271494ea7ac2ad503d6c5bb |
| institution | Directory Open Access Journal |
| issn | 2213-6711 |
| language | English |
| last_indexed | 2024-12-11T01:31:21Z |
| publishDate | 2018-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Stem Cell Reports |
| spelling | doaj.art-11f162d4b271494ea7ac2ad503d6c5bb2022-12-22T01:25:21ZengElsevierStem Cell Reports2213-67112018-07-011113242The Impact of APP on Alzheimer-like Pathogenesis and Gene Expression in Down Syndrome iPSC-Derived NeuronsDmitry A. Ovchinnikov0Othmar Korn1Isaac Virshup2Christine A. Wells3Ernst J. Wolvetang4Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, QLD 4072, AustraliaAustralian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, QLD 4072, AustraliaCentre for Stem Cell Systems, MDHS, University of Melbourne, Melbourne, VIC 3010, AustraliaAustralian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, QLD 4072, Australia; Centre for Stem Cell Systems, MDHS, University of Melbourne, Melbourne, VIC 3010, AustraliaAustralian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, QLD 4072, Australia; Corresponding authorSummary: 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. : Wolvetang and colleagues used CRISPR/Cas9 technologies to manipulate the copy number and expression of the amyloid precursor protein (APP) gene in Down syndrome and corresponding euploid pluripotent stem cells. They demonstrate that APP modulates the expression of a surprisingly large cohort of genes and dictates Aβ42/40 ratio and pyroglutamate-E3 foci but does not affect hyperphosphorylated forms of tau associated with Alzheimer disease or neuronal cell death of in vitro generated cortical neurons. Keywords: beta-amyloid, iPSC, Down syndrome, Hsa21 trisomy, CRISPR/Cas9, cortical neurogenesis, gene expression profiling, tau phosphorylationhttp://www.sciencedirect.com/science/article/pii/S2213671118302212 |
| spellingShingle | Dmitry A. Ovchinnikov Othmar Korn Isaac Virshup Christine A. Wells Ernst J. Wolvetang The Impact of APP on Alzheimer-like Pathogenesis and Gene Expression in Down Syndrome iPSC-Derived Neurons Stem Cell Reports |
| title | The Impact of APP on Alzheimer-like Pathogenesis and Gene Expression in Down Syndrome iPSC-Derived Neurons |
| title_full | The Impact of APP on Alzheimer-like Pathogenesis and Gene Expression in Down Syndrome iPSC-Derived Neurons |
| title_fullStr | The Impact of APP on Alzheimer-like Pathogenesis and Gene Expression in Down Syndrome iPSC-Derived Neurons |
| title_full_unstemmed | The Impact of APP on Alzheimer-like Pathogenesis and Gene Expression in Down Syndrome iPSC-Derived Neurons |
| title_short | The Impact of APP on Alzheimer-like Pathogenesis and Gene Expression in Down Syndrome iPSC-Derived Neurons |
| title_sort | impact of app on alzheimer like pathogenesis and gene expression in down syndrome ipsc derived neurons |
| url | http://www.sciencedirect.com/science/article/pii/S2213671118302212 |
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