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

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

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=17

YEAR=2024

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2024.1373568

DOI=10.3389/fnmol.2024.1373568

ISSN=1662-5099

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