APOE3 Christchurch modulates β-catenin/Wnt signaling in iPS cell-derived cerebral organoids from Alzheimer's cases
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APOE3 Christchurch modulates β-catenin/Wnt signaling in iPS cell-derived cerebral organoids from Alzheimer's cases. / 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.
In: FRONT MOL NEUROSCI, Vol. 17, 2024, p. 1373568.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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 - 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.
U2 - 10.3389/fnmol.2024.1373568
DO - 10.3389/fnmol.2024.1373568
M3 - SCORING: Journal article
C2 - 38571814
VL - 17
SP - 1373568
JO - FRONT MOL NEUROSCI
JF - FRONT MOL NEUROSCI
SN - 1662-5099
ER -
