The developmental expression and regulation of tau

Although best known for its role in Alzheimer disease, the tau protein is expressed throughout brain development. It remains unclear when during development this expression begins and which cell types this expression occurs in. Understanding this expression pattern could contribute new knowledge to how tau affects disease states in both fetal and neonatal periods.

To better address this gap in knowledge, we looked at the level of tau mRNA expressed in different cell types across various gestational ages and found that more mature cells in more mature regions of the brain expressed more tau mRNA. Additionally, we found that more mature regions of the brain expressed more tau protein. To study this in depth, we established two model systems that show a similar pattern of tau expression and would allow us to look at factors that control tau expression.

The first model system, SH-SY5Y cells, is an immortalized neuroblastoma cell line that can be differentiated into neurons. Using this model system, we found that a protein previously described to affect tau in mice, called HuD, also has an effect on tau in humans. When we removed the neuron’s ability to produce the HuD protein in an experiment called a knockdown, we found that tau protein significantly decreased.

The second model system, cortical organoids, is derived from human stem cells and forms a 3D structure that is similar in organization to the cortex of a human fetal brain. Using this model system, we found that the cortical organoids express a similar, consistent tau mRNA and tau protein pattern to the human fetal brain. This will allow future studies to use this model to address questions regarding regulation of tau that could provide new insight into therapeutics for neurodegenerative diseases.