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

Abstract

A patient with the <i>PSEN1</i> E280A mutation and homozygous for <i>APOE3</i> Christchurch (<i>APOE3Ch</i>) 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 <i>APOE3Ch</i>, 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 <i>APOE3Ch</i> expression. In the <i>APOE3Ch</i> cerebral organoids, we observed a protective pattern from early tau phosphorylation. ScRNA sequencing revealed regulation of Cadherin and Wnt signaling pathways by <i>APOE3Ch</i>, with immunostaining indicating elevated β-catenin protein levels. Further <i>in vitro</i> 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.