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

Topic: Brain proteins, microglia and lab models

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.

@article{ovchinnikov2018-29861166,
  author  = {Ovchinnikov, D. A. and Korn, O. and Virshup, I. and Wells, C. A. and Wolvetang, E. J.},
  title   = {{The Impact of APP on Alzheimer-like Pathogenesis and Gene Expression in Down Syndrome iPSC-Derived Neurons}},
  journal = {Stem cell reports},
  year    = {2018},
  doi     = {10.1016/j.stemcr.2018.05.004},
  pmid    = {29861166},
  url     = {https://doi.org/10.1016/j.stemcr.2018.05.004}
}

Key findings

• 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.

Why it matters

In Down syndrome induced pluripotent stem cell-derived neurons, deleting the extra copy of the APP gene reduced beta-amyloid production and amyloid aggregates but did not affect several tau-related Alzheimer's disease phenotypes or increased apoptosis. This is a cell-based study showing APP's role in amyloid aspects but challenging the idea that APP levels alone cause tau changes or neuronal death.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1016/j.stemcr.2018.05.004
• PubMed: 29861166
• Original source →
• Free full text: Stem Cell Reports →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

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• Comparison of CSF biomarkers in Down syndrome and autosomal dominant Alzheimer's disease: a cross-sectional study The Lancet. Neurology · 2021-08-01 · usefulness score 62/100 · shares: down, syndrome
• Comparison of amyloid burden in individuals with Down syndrome versus autosomal dominant Alzheimer's disease: a cross-sectional study The Lancet. Neurology · 2023-01-01 · usefulness score 60/100 · shares: down, syndrome
• Comparison of tau spread in people with Down syndrome versus autosomal-dominant Alzheimer's disease: a cross-sectional study The Lancet. Neurology · 2024-05-01 · usefulness score 67/100 · shares: down, syndrome

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