Data Sheet 2_Isogenic human stem cell models reveal mutation-dependent protective mechanisms of APOE3 Christchurch.pdf

The rare APOE3 Christchurch (APOE3ch) variant has been associated with delayed disease onset in a familial Alzheimer’s disease case, suggesting a potential protective role. However, the mechanisms underlying this protection, particularly across different genetic backgrounds, remain unclear.</p>Methods<p>We generated isogenic human induced pluripotent stem cell (hiPSC)–derived neural cultures harboring either PSEN1 E280A or amyloid precursor protein duplication (APPdp) mutations, with and without the APOE3ch variant, using prime editing.

Neural differentiation, amyloid-beta production, amyloid precursor protein processing, tau phosphorylation and transcriptomic profiles were assessed.</p>Results<p>APOE3ch did not affect neural differentiation or apolipoprotein E secretion. However, it exhibited mutation-dependent effects on Alzheimer’s disease phenotypes. In amyloid precursor protein duplication cultures, APOE3ch significantly reduced amyloid-beta production and shifted processing toward non-amyloidogenic pathways, accompanied by decreased phosphorylated tau.