Abstract
SummaryEarly-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.
Highlights
The APP gene encodes the amyloid precursor protein (APP) and is located on chromosome 21
Generation of APP Copy-Number-Normalized Down syndrome (DS) induced pluripotent stem cells (iPSCs) and Doxycycline-Inducible APP-Overexpressing Human Embryonic Stem Cells To address the role of the supernumerary copy of the APP gene in Alzheimer disease (AD)-like neuropathology in DS, we deleted exon 3
Of one of the APP alleles (Figure 1A) in a previously characterized footprint-free DS iPSC line, clone C11DS (Briggs et al, 2013) and this was confirmed by genomic PCR (Figure 1B) and Southern blotting (Figure 1C)
Summary
The APP gene encodes the amyloid precursor protein (APP) and is located on chromosome 21. Ab aggregation was previously linked to tau hyperphosphorylation, defective synapse function, oxidative stress, and increased neuronal cell death (Spires-Jones and Hyman, 2014). Consistent with these observations, three cases of partial trisomy of chromosome 21 that exclude the APP locus showed no evidence of earlyonset AD (EOAD) (Korbel et al, 2009) or neurodegeneration at an advanced age (Doran et al, 2017). DS iPSC-derived cortical neurons were previously shown to exhibit increased production of Ab42, and hyperphosphorylation and redistribution of tau (Chang et al, 2015), suggesting that DS iPSC-derived cortical neuronal cultures can recapitulate aspects of AD neuropathology in vitro (Shi et al, 2012)
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