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APOE3Christchurch modulates tau phosphorylation and β-catenin/Wnt signaling in iPS cell-derived cerebral organoids from Alzheimer’s cases

ABSTRACT: Alzheimer’s disease (AD) is the most common cause of dementia. A patient with the PSEN1 E280A mutation and homozygous for APOE3 Christchurch (APOE3Ch) was found to have extreme resistance to cognitive decline and tauopathy despite having high amyloid burden. We established induced pluripotent stem cell (iPS)-derived cerebral organoids from this resistant case and a non-protected control. We used CRISPR/Cas9 gene editing to remove or add APOE3Ch from these iPS cells to assess causality. We found a pattern of tau phosphorylation consistent with protection in APOE3Ch cerebral organoids. We identified Cadherin and Wnt signaling regulation by APOE3Ch through scRNA-sequencing and elevated β-catenin protein in APOE3Ch organoids as a potential mediator of protection against tauopathy. We have identified that ApoE3Ch acts as a Wnt signaling enhancer. Our study found that APOE3Ch is necessary and sufficient to confer resistance to tauopathy, a hallmark of AD. This establishes the premise for development of novel, protected case-inspired therapeutics for AD and tauopathies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE241453 | GEO | 2024/03/20

REPOSITORIES: GEO

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The APOE-R136S mutation protects against APOE4-driven Tau pathology, neurodegeneration and neuroinflammation

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2023-09-21 | GSE217854 | GEO

Single Nucleus RNA Sequencing Distinguishes an Autosomal Dominant Form of Alzheimer´s Disease from Sporadic Disease [spatial transcriptomics]

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Human Sandhoff Disease Cerebral Organoids Exhibit Enlarged Size, Increased Cellular Proliferation, and Impaired Differentiation

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2022-07-01 | E-MTAB-11438 | biostudies-arrayexpress

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2019-10-16 | E-MTAB-8228 | biostudies-arrayexpress

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Project description:Gene expression analysis of control fibroblasts (NFH2), one AD-derived fibroblasts (NFH-46), NFH2-derived control-iPS cells (OiPS3, OiPS6), NFH46-derived AD-iPS cells (iPS5 and iPS 26B), hESCs (H1 and H9).

2015-04-21 | GSE42492 | GEO

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