Stem Cell Reports
Volume 11, Issue 1, 10 July 2018, Pages 32-42
Journal home page for Stem Cell Reports

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

https://doi.org/10.1016/j.stemcr.2018.05.004Get rights and content
Under a Creative Commons license
open access

Highlights

  • Normalization of APP copy number in Down syndrome (DS) iPSCs

  • APP controls neuronal amyloid levels and pyroglutamate (pE3) accumulation

  • APP in DS neurons does not affect levels of neurotoxic tau species or apoptosis

  • APP gene dosage has stage-specific and genome-wide effects on gene expression

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.

Keywords

beta-amyloid
iPSC
Down syndrome
Hsa21 trisomy
CRISPR/Cas9
cortical neurogenesis
gene expression profiling
tau phosphorylation

Cited by (0)