Engineered Alzheimer Organoids Validate the Link Between Intracellular and Soluble p-Tau Biomarkers and Highlight the Contribution of Astrocytic Tau
- Neurosci Bull. 2026 Apr 11. doi: 10.1007/s12264-026-01615-4.
- 1. State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China.
- 2. University of Chinese Academy of Sciences, Beijing, 101408, China.
- 3. Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
- 4. Shanghai Key Laboratory of Signaling and Disease Research, Laboratory of Receptor-based Biomedicine, The Collaborative Innovation Center for Brain Science, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
- 5. Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- 6. State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China. [email protected].
- 7. University of Chinese Academy of Sciences, Beijing, 101408, China. [email protected].
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.