Christchurch Modulates β-catenin/Wnt Signaling in IPS Cell-derived Cerebral Organoids from Alzheimer's Cases

Overview

Journal Front Mol Neurosci

Specialty Molecular Biology

Date 2024 Apr 4

PMID 38571814

Authors

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 Aguillon

Marlene Jimenez-Del-Rio

Ana Baena

Diego Sepulveda-Falla

Francisco Lopera

Yakeel T Quiroz

Joseph F Arboleda-Velasquez

Randall C Mazzarino

Affiliations

Soon will be listed here.

Abstract

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

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