TY - JOUR
T1 - APOE3 Christchurch modulates β-catenin/Wnt signaling in iPS cell-derived cerebral organoids from Alzheimer’s cases
AU - Perez-Corredor, Paula
AU - Vanderleest, Timothy E.
AU - Vacano, Guido N.
AU - Sanchez, Justin S.
AU - Villalba-Moreno, Nelson D.
AU - Marino, Claudia
AU - Krasemann, Susanne
AU - Mendivil-Perez, Miguel A.
AU - Aguillón, David
AU - Jiménez-Del-Río, Marlene
AU - Baena, Ana
AU - Sepulveda-Falla, Diego
AU - Lopera, Francisco
AU - Quiroz, Yakeel T.
AU - Arboleda-Velasquez, Joseph F.
AU - Mazzarino, Randall C.
N1 - Publisher Copyright:
Copyright © 2024 Perez-Corredor, Vanderleest, Vacano, Sanchez, Villalba-Moreno, Marino, Krasemann, Mendivil-Perez, Aguillón, Jiménez-Del-Río, Baena, Sepulveda-Falla, Lopera, Quiroz, Arboleda-Velasquez and Mazzarino.
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
KW - Alzheimer’s disease
KW - ApoE
KW - ApoE Christchurch
KW - CRISPR
KW - Presenilin
KW - Wnt signaling
KW - iPS cells
UR - https://www.scopus.com/pages/publications/85189291772
UR - https://www.scopus.com/pages/publications/85189291772#tab=citedBy
U2 - 10.3389/fnmol.2024.1373568
DO - 10.3389/fnmol.2024.1373568
M3 - Article
C2 - 38571814
AN - SCOPUS:85189291772
SN - 1662-5099
VL - 17
JO - Frontiers in Molecular Neuroscience
JF - Frontiers in Molecular Neuroscience
M1 - 1373568
ER -