Ru Zhang1,5 · Xiaoxu Dong2  · Gang Pei1,3,4,5 · Shichao Huang1,5

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 Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China 

3 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 

4 Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China 

5 University of Chinese Academy of Sciences, Beijing 101408, China

Abstract

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.

Keywords

Alzheimer’s disease; Human chimeric brain organoids; Astrocytes; Tau pathology; p-Tau biomarkers

[Springerlink]