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

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 ß-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. Overall design: A patient with the PSEN1 E280A mutation and homozygous for APOE3 Christchurch (APOE3Ch) displayed remarkable resistance to Alzheimer's disease (AD) cognitive decline and tauopathy, despite having a high amyloid burden. To investigate the causal role of APOE3Ch in protection, we generated induced pluripotent stem cell (iPS)-derived cerebral organoids from this resistant case (designated "alpha" (a)) and a non-protected control (designated "omega" (?)), using CRISPR/Cas9 gene editing to modulate APOE3Ch expression. Both patients were from the PSEN1 (E280A) "Paisa" kindred.