| Autor: |
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 Aguillón, Marlene Jiménez-Del-Río, Ana Baena, Diego Sepulveda-Falla, Francisco Lopera, Yakeel T. Quiroz, Joseph F. Arboleda-Velasquez, Randall C. Mazzarino |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
|
| Zdroj: |
Frontiers in Molecular Neuroscience, Vol 17 (2024) |
| Druh dokumentu: |
article |
| ISSN: |
1662-5099 |
| DOI: |
10.3389/fnmol.2024.1373568 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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