2024 AIChE Annual Meeting

Influence of Glia on Tau Propagation Using Patient-Derived Tau Aggregates in a Triculture System

Tauopathies encompass a spectrum of neurodegenerative disorders marked by the aggregation of the microtubule-stabilizing protein tau. Prominent among these conditions are Alzheimer’s Disease (AD) and frontotemporal dementias, characterized by neuronal cell death resulting from the propagation of aggregated tau. There are 26 types of aggregated tau, each of which with a different morphology that determines how it propagates throughout the brain. Understanding the molecular mechanism through which these aggregates spread is essential to designing effective treatment strategies. Previous research has focused on developing animal models to understand the spread of tauopathies. However, this research is often costly while making little progress in treatment strategies: what might be valid in a mouse often fails in humans. In vitro human stem cell-based models offer a viable alternative, being a lower-cost and more genetically representative alternative to mouse models that have led to so many failed clinical trials. While no model can adequately represent every function of the human brain, the field hopes that these human cell-based models can fill in gaps that other systems miss.

Many in vitro models in the literature utilize neurons, astrocytes, and microglia to provide an accurate representation of the brain cortex’s natural physiology. Astrocytes and microglia are types of glia, which provide immunity and support to neurons. Glia are thought to play a role in how tauopathies spread throughout the brain, but evidence of glia-directed propagation is not well known. Understanding the role of glia is essential to designing effective treatment strategies, as glia are responsible for clearance of protein aggregates, and reactive glia are responsible for pruning of neuronal synapses.

We are building a 3D tau propagation model to answer whether glia play a role in the spread of pathological tau through the human brain. This system consists of AD patient brain-derived protein aggregates (with age-matched controls) which validates tau seeding activity of our cohort through a FRET-based tau biosensor. Within a neural triculture of induced pluripotent stem cell (iPSC)-derived neurons, microglia, and astrocytes, we treat glia with patient-derived tau and then re-plate them with untreated neurons to observe whether glia can propagate uptake aggregated tau into neuron bodies. To model a 3D matrix of cortex tissue, we then embed our triculture in Matrigel to observe tau propagation across a 3D network of cells.

Preliminary results have demonstrated that protein derived from patient brains contains seed-positive tau. When dosed in a triculture, this tau impacts the survival and morphology of neurons and glia. Future directions include testing in different hydrogel types, which provide different support matrices for cell growth. Previous work by our group demonstrates enhanced viability and maturation of cortical dopaminergic neurons in GelMA and GelMA-Cad compared to other hydrogels. We intend to explore the growth of our iPSC-derived neurons under similar conditions. We will also test other cell types involved in the neural immune environment, such as T cells and other macrophages.