Increased Tau Expression Correlates with Neuronal Maturation in the Developing Human Cerebral Cortex

Abstract

Although best known for its role in Alzheimer disease, tau is expressed throughout brain development, though it remains unclear when and which cell types this expression occurs and how it affects disease states in both fetal and neonatal periods. We thus sought to map tau mRNA and protein expression in the developing human brain at the cellular level using a combination of existing single cell RNA sequencing (sc-RNAseq) data, RNA in situ hybridization (RNAscope), and immunohistochemistry (IHC). Using sc-RNAseq, we found that tau mRNA expression begins in radial glia but increases dramatically as migrating neuronal precursors mature. Specifically, TBR1⁺ maturing neurons and SYN⁺ mature neurons showed significantly higher mRNA expression than GFAP⁺/NES⁺ radial glia or TBR2⁺ intermediate progenitors. By RNAscope, we found low levels of tau mRNA in subventricular zone radial glia and deep white matter intermediate progenitors, with an increase in more superficially located maturing and mature neurons. By total-tau IHC, the germinal matrix and subventricular zone showed little protein expression, although both RNAscope and sc-RNAseq showed mRNA, and western blotting revealed significantly less protein in those areas compared with more mature regions. Induced pluripotent stem cell (iPSC)-derived cortical organoids showed a similar tau expression pattern by sc-RNAseq and RNAscope. Our results indicate that tau increases with neuronal maturation in both the developing fetal brain and iPSC-derived organoids and forms a basis for future research on regulatory mechanisms triggering the onset of tau gene transcription and translation, which may represent potential therapeutic targets for neurodegenerative tauopathies and neurodevelopmental disorders.

Significance Statement Tau is a mediator of neurotoxicity across multiple neurodegenerative diseases, including Alzheimer disease and chronic traumatic encephalopathy. With the recent failure of β-amyloid-targeted therapies in AD to improve cognitive function, there is increasing interest in tau targeted therapies. Tau is expressed throughout brain development, but the function and normal developmental expression remains unclear. Here, we demonstrate that tau expression begins early during neuronal maturation in both human fetal brain and iPSC-derived cortical organoids. This work forms the basis for future research into the developmental regulation of tau expression which may provide future tau-related therapeutic targets.