APOE3 Christchurch modulates β-catenin/Wnt signaling in iPS cell-derived cerebral organoids from Alzheimer’s cases

Paula Perez-Corredor, Timothy E. Vanderleest, Guido N. Vacano, Justin S. Sanchez, Nelson D. Villalba-Moreno, Claudia Marino, Susanne Krasemann, Miguel A. Mendivil-Perez, David Aguillón, Marlene Jiménez-Del-Río, Ana Baena, Diego Sepulveda-Falla, Francisco Lopera, Yakeel T. Quiroz, Joseph F. Arboleda-Velasquez, Randall C. Mazzarino

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

A patient with the PSEN1 E280A mutation and homozygous for APOE3 Christchurch (APOE3Ch) displayed extreme resistance to Alzheimer’s disease (AD) cognitive decline and tauopathy, despite having a high amyloid burden. To further investigate the differences in biological processes attributed to APOE3Ch, we generated induced pluripotent stem (iPS) cell-derived cerebral organoids from this resistant case and a non-protected control, using CRISPR/Cas9 gene editing to modulate APOE3Ch expression. In the APOE3Ch cerebral organoids, we observed a protective pattern from early tau phosphorylation. ScRNA sequencing revealed regulation of Cadherin and Wnt signaling pathways by APOE3Ch, with immunostaining indicating elevated β-catenin protein levels. Further in vitro reporter assays unexpectedly demonstrated that ApoE3Ch functions as a Wnt3a signaling enhancer. This work uncovered a neomorphic molecular mechanism of protection of ApoE3 Christchurch, which may serve as the foundation for the future development of protected case-inspired therapeutics targeting AD and tauopathies.

Original languageEnglish (US)
Article number1373568
JournalFrontiers in Molecular Neuroscience
Volume17
DOIs
StatePublished - 2024
Externally publishedYes

Keywords

  • Alzheimer’s disease
  • ApoE
  • ApoE Christchurch
  • CRISPR
  • iPS cells
  • Presenilin
  • Wnt signaling

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience

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