In:
Frontiers in Molecular Neuroscience, Frontiers Media SA, Vol. 17 ( 2024-3-20)
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1662-5099
DOI:
10.3389/fnmol.2024.1373568
DOI:
10.3389/fnmol.2024.1373568.s001
DOI:
10.3389/fnmol.2024.1373568.s002
DOI:
10.3389/fnmol.2024.1373568.s003
DOI:
10.3389/fnmol.2024.1373568.s004
DOI:
10.3389/fnmol.2024.1373568.s005
DOI:
10.3389/fnmol.2024.1373568.s006
Language:
Unknown
Publisher:
Frontiers Media SA
Publication Date:
2024
detail.hit.zdb_id:
2452967-9
Permalink