Engineered Alzheimer Organoids Validate the Link Between Intracellular and Soluble p‑Tau Biomarkers and Highlight the Contribution of Astrocytic Tau
Engineered Alzheimer Organoids Validate the Link Between Intracellular and Soluble p‑Tau Biomarkers and Highlight the Contribution of Astrocytic Tau
Soluble phosphorylated tau has become a key biomarker for Alzheimer’s disease pathology, yet further mechanistic studies are needed beyond observational investigations to clarify the relationship between soluble p-tau species and intracellular tau pathology. Here, we utilized chimeric human cerebral organoids (chCOs) to generate a series of organoids in which the endogenous MAPT gene was CRISPR/Cas9 edited in different cell types to create phosphorylation-deficient mutants at the AD-associated sites. We found that the APPswe mutation increased tau phosphorylation in both neurons and astrocytes. Notably, astrocyte-specific phosphorylation-deficient mutations of tau in organoids reduced soluble p-tau181 and p-tau217 levels, as detected by single-molecule array. These findings indicate that astrocytic tau plays a substantial role in contributing to the pool of extracellular phosphorylated tau and suggest it may be an overlooked source of AD biomarkers. Moreover, our engineered chCOs offer a versatile platform for exploring how cell-type-specific pathologies correlate with changes in biomarker profiles.